Bioavailability - Science topic

Hi,

You may make an inquiry at Alfa Chemistry, they offer you advices and kinds of good-quality chemicals.

The initial distribution phase has a half-life of approximately 1 hour, although it may range up to >3 hours. (...) The initial distribution phase is followed by a prolonged terminal elimination phase (half-life up to 48 hours). The terminal elimination half-life of the active metabolite N-desmethyldiazepam is up to 100 hours. (...) Elimination half-life increases by approximately 1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age.

As you know situation is quite dynamic and complicated ....

Tmax = 1.25h + initial elimination half-life =1h next phase half life= 3h and elimination/terminal =20h (if 20 years old patient).

I think this paper (which covers an oral dose of 5 mg) shows PK profile could be useful.

https://pubmed.ncbi.nlm.nih.gov/6849499/#:~:text=Absolute%20bioavailability%20averaged%2094%25%2C%20indicating,sex%20significantly%20influenced%20oral%20absorption.

From my raw estimation 14 h after a single dose of 2 mg per os in saliva it should be around 1 ng/mL but it's not based on an exact analysis of raw data please double-check....

I hope it helps in your investigation ....

Tomasz

Wow. Thanks so much for the good recommendations sir.

I will check them out.

Iron extraction from plants can be a complex process due to the presence of iron in various forms, such as inorganic salts, heme complexes, iron-protein conjugates, and iron-polysaccharide complexes. Extracting iron in its natural form from plants can enhance its bioavailability and make it more accessible for human consumption.

There are several techniques that can be used for the total extraction of iron from plants. Here are a few commonly employed methods:

Acid extraction: This method involves treating the plant material with acid, such as hydrochloric acid or sulfuric acid, to dissolve the iron compounds. The resulting solution can be further processed to isolate the iron.

Chelation: Chelating agents like ethylenediaminetetraacetic acid (EDTA) or citric acid can be used to complex and solubilize the iron from plant material. The chelating agent forms stable complexes with iron, making it easier to extract.

Enzymatic extraction: Certain enzymes, such as cellulases or pectinases, can be used to break down plant cell walls and release iron from iron-polysaccharide complexes. Enzymatic methods are more specific and can help target specific iron complexes in plants.

Protein extraction: Protein extraction techniques, such as solubilization using detergents or organic solvents, can be employed to extract iron-protein conjugates from plant sources. These methods aim to disrupt the protein structure and release the iron bound to proteins.

It's important to note that the choice of extraction method depends on the specific plant material, its iron composition, and the desired form of iron extraction. Additionally, optimizing extraction conditions, such as temperature, pH, and extraction time, can also influence the efficiency of iron extraction.

When dealing with bioavailable arsenic (As) in acid soils, it is important to use extraction methods that are suitable for such conditions. Here are two commonly used extraction methods for bioavailable As in acid soils:

1. Mehlich-3 extraction: The Mehlich-3 method is widely used for extracting various nutrients and trace elements from acidic soils. It involves the use of a mixture of strong acids (such as hydrochloric acid and sulfuric acid) at a pH of approximately 2.5. This method is effective for extracting bioavailable As in acid soils and is commonly used in agricultural and environmental research.

2. Modified Morgan extraction: The Modified Morgan method is another commonly used extraction method for assessing bioavailable As in acid soils. It utilizes a mixture of weak acids, including acetic acid and ammonium nitrate, at a pH of approximately 4.8. This method is suitable for acidic pH and has been used extensively for extracting bioavailable As in both agricultural and contaminated soils.

Regarding the specific Soil As extraction method using 0.5M NaHCO3 at pH 8.5, it is not suitable for acidic pH conditions. Sodium bicarbonate (NaHCO3) at pH 8.5 is typically used to extract As in neutral to slightly alkaline soils. The higher pH helps in solubilizing As from solid phases. However, in acidic soils, the use of NaHCO3 at pH 8.5 may not be effective for extracting bioavailable As due to the low pH of the soil.

It is recommended to choose an extraction method that is appropriate for the specific pH conditions of the soil you are working with. The Mehlich-3 or Modified Morgan extraction methods mentioned above would be more suitable for acidic pH soils.

Use computational data of PubChem to better understanding values.

Quercetin is a flavonoid that has been extensively studied for its anti-inflammatory properties. However, its low bioavailability is a constraint for its medical use. Isoquercetin and dihydroquercetin are two derivatives of quercetin that have been proposed as potential alternatives due to their improved bioavailability and clinical effectiveness.

Isoquercetin is a glycoside of quercetin and is better absorbed in the gut, which means that more of it reaches the bloodstream and can be utilized by the body. Dihydroquercetin is a hydrogenated form of quercetin, which has been suggested to be more clinically effective than quercetin. It is worth noting that while these derivatives may have improved bioavailability, there is limited clinical data available on their safety and efficacy. Therefore, more research is needed to fully understand the benefits and risks of these molecules.

1. Spuway extraction is a method of extracting bioavailable nutrients from plants by subjecting the sample to high-temperature steam, which removes much of the plant material but leaves the nutrients intact. CAT+ extraction is a method of extracting bioavailable nutrients from plants by using a combination of high-temperature steam, chemical solvents, and mechanical force to break down the plant material and extract the nutrients.

2. Spuway extraction is a rapid method that can be done in under an hour, while CAT+ extraction is a slower process that can take several hours.

3. Spuway extraction is more efficient at extracting heat-sensitive compounds, while CAT+ extraction is more efficient at extracting compounds that are resistant to heat.

4. Spuway extraction produces a more concentrated solution, while CAT+ extraction produces a less concentrated solution.

5. Spuway extraction is more expensive than CAT+ extraction.

Use nanosuspension Technology

Particle size Reduction

pH adjustment

A new chemical component entity cannot be directly tested in vivo with experimental animals, beforehand it needs to be examined carefully in-silico regarding the estimation of protein binding, free energy Gibbs, and toxicity to target cells with in-vitro culture cell. If it is confirmed that it is safe and provides better activity than the previous product. Testing with experimental animals can be done.

Is it the absolute BA or Relative BA? I think you may check the method of calculation. The machanism of saturated in clesrance pathway may be possible.

I hope these files can be useful for you.

According to Singh et al., the typical mean Pb concentration for surface soils worldwide averages 32 mg/kg and ranges from 10 to 67 mg/kg. However, the value of Pb obtained from Raja Musa soil in this study is lower than in previous studies [37, 38], with 100 mg/kg suggested as the upper limit

(PDF) Heavy Metals and Ni Phytoextractionin in the Metallurgical Area Soils in Elbasan (researchgate.net)

Check https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3918523/

Hi,

In some species marbofloxacin exhibit flip-flop phenomenon after SC administration. It means the absorption phase is longer than elimination and affects Kel. In such a case you can see supra-bioavailability in your study. The question is did you see differences between Kel IV versus IM and/or SC. Of course please remember you can compare such values if your sampling was long enough - according to the roles. Some researchers make to short sampling and after that refer to "two-stage" elimination which is not true observation. So if you take samples long enough then it's possible to verify flip-flop.

Rules:

Example flip-flop:

Finally, the question is about milking. If it was milking cows it could be a source of difference. Milk concentrations of marbofloxacin and disposition to the udder are dependent on the concentration of the drug in blood plasma. So after IV whole free fractions of the drug in plasma is available for distribution into the milk (it's quite a huge compartment) and for example when 12 hours after drug administration the cows are milked, whole that fraction is eliminated. But another situation is after SC or IM especially if the absorption process is long because finally after for example 12 h when cows are milked different fraction (in comparison to IV) is eliminated with milk.

For flip-flop verification:

First you should make comparison Kel between IV IM and SC

Next compare kab with Kel for IM and SC

It's only a general comment because I don't know the details of your study ....

Best regards,

Tomasz

As there are many HPLC methods for AA, it is rather important that you share with us which of the many procedures and methods you will use. For the very commonly used OPA/FMOC procedure, many choices for ISTD exist. Examples would include: sarcosine and/or norvaline.

Dear Uma Nath Shukla Phytic acid is the major storage form of phosphorous in cereals, legumes, oil seeds and nuts. Phytic acid is known as a food inhibitor which chelates micronutrient and prevents it to be bioavailabe for monogastric animals, including humans, because they lack enzyme phytase in their digestive tract. Several methods such as genetic improvement as well as several pre-treatment methods, viz., fermentation, soaking, germination and enzymatic treatment of grains with phytase enzyme may be employed to address the issue of this antinutrient. For details, please go through the below mentioned link:

Thanks!

اSuggested use

Volcanic Rock Dust

The percentage of the drug that is not bound (55%) is free to reach the receptor (Brain) to cause the effects or to be eliminated from the body. The effects on the brain would suggest that the drug is lipid-soluble, but that is not guaranteed, as it appears to have been administred intrathecally (doesn't have to be fat-soluble) or intravenously if bioavailability is 100%. Fat soluble drugs may remain in the system longer if the patient has a soluble higher fat body composition. I am not clear if the question refers to 60-70% eliminated unchanged if a fraction of 100% that is bioavailable, or part of the 55% that is not bound.

The answer is highly dependent on the nature of the drug administered, site, route of administration, and the route of elimination. For example, if the drug is eliminated in the kidneys through organic acid transporters, one could exploit competitive inhibition with a compound that uses the same transporter. For Eg Penicillin and Probenecid combined to increase concentration and duration of action of the penicillin. The probenecid is eliminated and the penicilin is retained. The repeat dose is dependent on the indication of the drug, how long the effects of the drug is required, or the drug elimination rate. If it is an antibiotic; whether it utilizes concentration or time-dependentare killing effect.

One needs to consider the specific drug and clinical scenario you have in mind to give a definitive answer.

That depends on the sample type. Storing at at -20 degrees Celsius should maintain the integrity of most plant protein hydrolysate for a few months if the containers are air tight. However, if polyphenols are still a contributing factor to the observed bioactivity, you will also have to protect the hydrolysates from light as well (using amber bottles or aluminum foil works) and measure quickly as they tend to lose bioactivity faster then purified proteins

Dear all, solubility depends on the chemical structure and types of existing intermolecular forces. Excessive sonication may degrade any of the compounds present in the recipe. There are many techniques to solubilize poorly soluble drugs. Please check the following links. My Regards

exactly it increases excretion of susceptible drugs as long as the concept of susceptible Prodrug has not been used

Chromium picolinate, specifically, has been shown to reduce insulin resistance . Chromium levels decrease with age. Studies show that people with type 2 diabetes have lower blood levels of chromium than those without the disease

https://books.google.az/books?id=uyQXqQH4NAMC&pg=PA3509&lpg=PA3509&dq=Is+it+scientifically+appropriate+to+dose-normalise+non-linear+compound+kinetics?&source=bl&ots=YTL-kUHvtf&sig=ACfU3U1_fCwMN0vTK-XFBkfEmSU07-nTCw&hl=ru&sa=X&ved=2ahUKEwiUm8ychKPqAhVLhqQKHd1-BVgQ6AEwAXoECAoQAQ#v=onepage&q=Is%20it%20scientifically%20appropriate%20to%20dose-normalise%20non-linear%20compound%20kinetics%3F&f=false

I Agree With Nabaa Sattar

you can use rabbit or dog for this purpose.

Thank you very much

Dear Nurrahmi Dewi Fajarningsih;

Please refer to the following RG answer which deals with this topic.

Dr. Diosady at the U of Toronto have worked extensively with this kind of separation using membrane processes, in chish it can be removed up to 80-90% of phenols.

In their method they use alkaline extraction followed by isoelectric precipitation, coupled to ultrafiltration and diafiltration processes to concentrate and purified the protein extracts. In a study by Xu et al. 2000 it was reported that about 50% of the total phenols were unbound at the extraction pH (alkaline). A treatment with 0.05 M NaCl could break phenolic-protein complexes ionically bonded accounting for about 30% of the the phenols in the extract. Finally a 0.1% SDS treatment can release nearly 25% of the condensed tannins which are bounded to proteins by hydrophobic interactions.

Hope this helps. Regards

There is your answer. http://pharmacopoeia.ru/en/obrashhenie-lekarstv-v-evrazes-demo/pravila-provedeniya-issledovanij-bioekvivalentnosti-lekarstvennyh-preparatov-v-ramkah-evrazijskogo-ekonomicheskogo-soyuza/

I appreciate your answer Mr. Luiz Querino Caldas

Your answer is clear. Large molecules that do their action in GI tract could be candidate for your question.

Interesting question and extremely pertinent. Please have a look on the following resources focussing on this issue:

1.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709506/

2.https://www.jstor.org/stable/24110574?seq=1#page_scan_tab_contents

3.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983620/

4.https://www.mdpi.com/journal/molecules/special_issues/Antitumor_Anti-HIV

5.https://juniperpublishers.com/jojiv/pdf/JOJIV.MS.ID.555556.pdf

6.https://www.intechopen.com/books/pharmacognosy-medicinal-plants/natural-products-in-drug-discovery

7.https://pubs.acs.org/doi/10.1021/np000399

8.https://www.liebertpub.com/doi/full/10.1089/aid.2017.0232

What a lot of parrots in here. Not one person has given a detailed explanation of what happens to the dose on crushing for the purpose of rapid release.

What would be the effective dose then, and why would it necessarily be dangerous?

Mostly the responses on here could have just as easily have been read off the packet.

You can use biosensors (microbes) to evaluate bioavailability in environmental samples:

For example, you could build a mass-balance where you measure As in water, then the bioavailable fraction to microbes, then measure how much gets into plants and where it goes.

For humans, as Gunawan stated, blood and urine (also toe nails). But these samples have to be collected soon after exposure.

Many animal studies were done in the 90ies. When it comes to arsenic, animals are more "tolerant" to arsenic and often need far greater exposure doses. Here is a good review paper on this topic:

Dear Ibrahim A Komeil,

Important to explain distribution of the drug and metabolites into tissues or organs is knowledge about concentration of the molecule in the analysed organ/tissue. Without metabolites standards you cant check what is concentration of the metabolite in selected organs. So you cant say what percent of the drug is available for the organ in specific time point. Please remember its dynamic process. That means in any time point (for example after single dose) concentration of the drug and metabolites changing not only in blood plasma but changing in all organs and tissues which are available for that drug and metabolites. See example on table 1:

Moreover metabolites distribution not must be correlated by linear way with drug elimination (if I correctly understand your question) especially if there is more than one metabolite and more than 1 organ tissue were distribution ongoing. Many different mechanisms can make difficult to analyse metabolites profiles (enantioselective metabolism, enterohepatic circulation of the metabolites etc.). So best idea to explain metabolites distribution is analysis in organs based on appropriate analytical standards.

Some documents at link below could be useful for you especially related to some aspects of methodology.

https://www.ema.europa.eu/en/vich-gl48-studies-evaluate-metabolism-residue-kinetics-veterinary-drugs-food-producing-animals

Best regards,

Tomasz

I don't think , any such equation is developed to my knowledge.However , cause and effect relationship is well documented...

In general, Cd bioavailability in plants is influenced by soil (medium) pH, temperatures, organic acid secretion by roots, the presence of chelating substances and other cations.

Hi Abraham Pappoe ,

I agree with what everyone is saying here but we have tried a number of other chelating agents both to keep some metals, such as Fe, in solution and to decrease bioavailability to bacteria that may be pertinent to your work (mind you, my expertise is really in mercury).

You can try:

- Nitrilotriacetic acid (NTA), a common reagent in growth medium trace element stock solutions

- citrate, a simple small organic acid that can chelate metals

- cysteine, or any thiol-bearing molecule really. The reduced sulphur groups tend to have a high affinity for many metals (which is also how metals exert a lot of their toxicity by denaturing these bonds in proteins). At very high concentration of cysteine is can also generate reduced sulphur that can favour precipitation of metals.

- naturally occurring dissolved organic matter is also a good way to reduced bioavailability of metals, given sufficient time for the metal-organic matter complex to age and form strong bonds. While this is difficult to control it can be a good option in natural environments

We used citrate in the following paper to control the availability of Fe:

I hope this helps, looking forward to continuing this discussion!

Vit Mateju , Nafees Mohammad, Mahmood M. Barbooti , Omar Ali Al-Khashman Mala Babagana Gutti and @ thanks very much for your reply, thinking on your countries of origen, would you agree with William McMinn that :

?

On the other hand, regarding about what to measure?, the remediation work would be to safeguard the ecosystem and therefore it would be important to measure Bioavailability and model the possible flow in the system, otherwise the toxicity and risk assestment wont be realistic. Moreover, even when toxic substances are on the natural level for a region, that does not mean they are not a danger.

Thanks a lot Jake !

Hi,

If you have different doses tested for a BA of course you have to dose normalize your PK parameters, i.e. devide on the dose given. This is applicable for dose related parameters, such as AUC, Cmax. Not applicable for time related parameters (tmax, t1/2) and for PK parameters calculated using dose already (CL, Vz).

An other advise, use geometric (or LS) means to compare and not average. Consequently, use CI instead of SD (or CV%) which is related to LS mean.

It depends on the toxic metal concentration of the soil and plant type, if the toxic metal content was below than tolerable level of certain plant, no need to control the availability of toxic metals.But, In the case of toxic metal surpassed tolerable level, you need to control the mobility in order to let the accumulation plants live in the substrata. no need to much worry about metal availability after the treatment, only the accumulation plant grow relatively well, plant rhizosphere will mobilize the metal

Well Leona. You are absolutely right. Sometime, people make it hike. However, it has potential and needs a lot of research including identification of the species for human consumption and food safety. Thereafter, we can go for extraction of polysaccharides or other bioavailable compounds. I am really interested on the subject and if you have carried out some research let me inform we can do some collaborative work.

Dear Sara,

If you make a comparison two PK profiles after IV administration (for example bolus with the same dose and drug substance but from different vendors) still you make comparison of data which reflects two fully available products. Its not bioavailability study because both substances immediately after injection are in the bloodstream. Its not absolute F analysis (because its not IV versus oral for example) and its not relative F (because its not subcutaneous versus intraperitoneal for example). You can name your analysis "relative F" only in case when IV is not available. Please check page 3 of this document:

Hope it will be useful, best regards

Tomasz

Yes, it is worthwhile. Polar compounds can efficiently reach tissues by loading them on different carriers. It is no more restricted to only structural modifications.

Generally, IP in a rodent is similar to IV so first-pass through the liver may be diminished. What fraction is absorbed after gavage, e.g., PO, will mostly see first-pass hepatic elimination. But, there are quite a few caveats in such generalizations. IP ~ IV is less likely as the molecule size increases, i.e., large pepides. Or, some molecules are not cleared rapidly by the liver and some have first-pass clearance by the intestine. Always best to measure blood or plasma exposure with time when comparing two diff routes of admin.

Larson has answered a few thing, so I am focusing here on your later question i.e. when can you say that your amendment is effective. In general , if your amedment is not working for all metals owing to several reasons as Larson explained you can calibrate your target soil or waste as no soil is supposed to have all the metals that you have selected for this study. Secondly, you can go with iterations in mixture used for amedment like in this case you are using only iron oxides you can add some more material there like biochar to find a perfect composite like in our to be published work we mixed alginate, MnO2 and activated carbon. Overall there is no single magic wand to decrease bioavailability of all metals in a single matrix.

Oral or dietary polyphenols that appear in the Urine, after ADME (absorption, distribution, metabolism and excretion) are assumed to be bioavailable (BV). In a agreement with Professor Shi, metabolims of polyphenols could lead to "underestimation" of the bioavailability. So "urinary bioavialablity" is the lower estimate whist the actual could be grater? In principle, to improve the accuracy of BV determinations the excreted (Urinary) value should combine the net concentration of all metabolites and non-metabolized polyphenols (not easy to measure).

Alternative measures of bioavailabilty exist as you know.

Pharmacolgists define BV as; = Area under curve -with oral route/ Area under curve IV route.

Nutrition scientists consider "digestbility" or Retention as more relevant or practical. Nutrient digestbility = 100*(Intake - (Feceal + Urinary)/ Intake.

I have not thought much about this but, I think the general concensus is that all current definitions and measures of BV have some limitations (?). It would be interesting to see what others think.

I presume that you are specifically interested in the oral route of delivery and will provide few thoughts with the oral route in mind.

According to the biopharmaceutical classification system (BCS), peptides and proteins are classified (mainly) as class III compounds. i.e. their oral bioavailability is limited by their membrane permeability. Whilst this may sound as an over simplification of the problem but in reality that is what limits oral absorption of such compounds. Research on developing an oral formulation of insulin is well over 4 decades old and up to this day, insulin is still not available as an oral dosage form, although there has been some break-throughs with other routes of delivery:

Vaccines and their oral delivery is another area where formulations scientists are challenged (in some cases) to deliver peptides / proteins via the oral route.

Liposomes (theoretically) would improve oral absorption of such compounds, simply because they are lipid vesicles and as such are more capable of permeating through GI tract wall. The problem though, is uploading liposomes with clinically meaningful amounts of water-soluble drugs which is rather limited.

The other important aspect that needs to be considered when thinking about oral delivery of proteins and peptides is their vulnerability and susceptibility to degradation in the GI tract. This mainly due to effect pH (the answer above addresses how this could be overcome using pH-responsive polymers) or due to enzymatic degradation (amidases, peptidases, proteases etc).

A combination of coating with pH-responsive polymers, incorporation into lipid based systems (such as SMEDDS, liposomes or Nano / microemulsions) along with using appropriate enzyme inhibitors could work.

Ibuprofen also has a bad/burning taste which would need to be masked for such a product. As answered above, there will be no performance improvement since a simple tablet is quickly and effectively absorbed. With all of the competition, it would take a large and expensive marketing campaign to have good sales which would likely not be economically viable with the low price margin.

Thank you for your responses but I don't think so that European comitee can accept all FDA notices. Phytase from A.niger is not accepted in food nutrition in France.

Thanks due to your questions. Only few geo chemical species of metals (for example water soluble, exchangeable, carbonate bound, Fe-Mn bound and organic material bound) are labile/bio-available i.e., fraction of metals that can be available to the organisms.

As you are interested to investigate the concentration of Hg in the water soluble fractions and exchangeable fractions ., the possible methods are as follows;

1. Water soluble fraction can be separated using water or hot water following Svete et al. (2000);

2. Exchangable fraction (using 1 M ammonium acetate or 0.01–0.5 M calcium chloride; pH 7 ) following Tessier et al. (1979).

>>Svete, P., Milacic, R., & Pihlar, B. (2000).Annali di Chimica, 90(5–6), 323–334 Rome.

>>Tessier, A., Campbell, P. G. C., & Bisson, M. (1979).Analytical Chemistry, 51(7), 844–851

I think we need to remember we are treating a patient. If the person really needs a treatment we should not deny them simply because we can't find the same brand. Most of the time the differences between brands are smaller than the differences between individuals, so It is entirely logical to give the patient a trial of a different brand and to watch what happens. So, my recommendation is to switch brands ( my own GP does it all the time) but ensure that the patient knows and is on the lookout for any differences that could be due to a change in pharmacokinetics such as an initially more intense effect (eg: Higher Cmax in an antihypertensive) or delayed effect (Later Tmax).

For any market

Hi, tail vein sampling under anesthesia might be considered but you should check the effect of anesthetic drug on your results.

Regards

Hi Sisira - there are a few approaches depending on resources / use. This can range from determining filterable metals (more useful than total), to labile measurements (such as Chelex labile - shown to be correlated with ecotoxic effects at least for Cu - see

and other work by these authors - particularly Simon Apte), to chemical speciation models to biotic ligand models (a few developed in N. America and Europe (see http://bio-met.net/)

Thank you Professor Happerly for your anwers and thank you dr Sarwar for this important topic.

thank you sir

Shereen,

The FDA has a well written and comprehensive guidance document on bioavailability (BA) and bioequivalence (BE) studies:

Both BA and BE studies characterize the pharmacokinetics of a compound based on the parameters of AUC, Cmax, Tmax, Cmin and others. Per FDA guidance, at minimum, the 90 percent confidence interval (CI) for both AUC and Cmax must be within 80 - 125 percent. For certain molecules, it may be necessary to have other parameters fall within this 80 - 125 percent range (examples could be antibiotics where Ctrough drives efficacy, or sustained release products).

In the following FDA guidance, the FDA provides specific examples when Ctrough might be important for demonstrating BE:

"For extended release formulations intended for repeated dosing, demonstration of BE should be based on multiple dose studies if there is accumulation between doses (i.e., if there will be at least a 2-fold increase in drug concentrations at steady state as compared to that observed after a single dose). In such cases, the Ctrough could be an important parameter to consider, in addition to Cmax and the AUC."

(https://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM415697.pdf)

Overall, I think it is fair to say that BA is determined, at minimum, by both AUC and Cmax.

Measure directly by ICP-MS.

You may use Caco2 Cell with any growth media But this cell membrane, you need to observe while you are changing media. Significant changes in cell line cant promote the change in media.

Hello, its indeed pleasure to have such discussion. I would like to bring back the focus of all to one of the commentary/paper published by nature entitled as "Deceptive curcumin offers cautionary tale for chemists" (https://www.nature.com/news/deceptive-curcumin-offers-cautionary-tale-for-chemists-1.21269) indicating that all the work on curcumin is waste. However, my own experience doesnt allow me think so, but looking closely it is the chemists and biologists who are of that opinion. However, time is apt for formulation scientists to come in and change this aspect.

Inviting your views on how to achieve that..

Please check the PDF attachments.

Prof Sabine Kulling - Max Rubner Institute in Karlsruhe 

The attached research papers may help you. 

Thank you very much Jean-Michel... 

I hope you have a good time..

Stay blessed

Kind regards

Benzyl peroxide (BPO) available as a combination with both of clindamycin and adapalene in India. . However if somebody use clindamycin twice in a day time . . I prefer to use BPO and adapalene combination once a night for 15-20 mins for Grade I/II Acne (IAA) . . Both having massive irritant potential even if use for short contact therapy . . If irritation is profuse . . You can prescribe BPO 2.5% soap once or twice 

1) If the dose of cyclosporine is low (5-10 mg), then make sustained release delivery....sustained delivery minimize variation

2) If dose is high, govern the dissolution by formulation property but not due to bile salts..e.g. solid dispersion with Lutrol polymers

3) Change absorption window

Did you gave same dose for IV/IM/Sc?

Bioavailability more than 1 (more than 100%) is a common phenomena, not only in i.p. and Sc but also in oral administration. F greater than 1 is relative to i.v. administration and assuming that in any of the routes compared, Clearance does not change. This is a big assumption and many a times rate of elimination is controlled by rate of absorption. Thats what happens in im/ip/Sc. or sustained release dosages.

During regular NCE research it has been observed that with same vehicle when, an NCE was administered i.v. and orally, Fwas greater than 1.

This can be due to many reason.

Detailed investigation can be done as in following paper published in two parts. These papers are must read.

1. xenobiotica, april 2004, vol. 34, no. 4, 353-366

Apparent absolute oral bioavailability in excess of 100% for a vitronectin receptor antagonist (SB-265123) in rat. I. Investigation of potential experimental and mechanistic explanations

K. W. WARD*, L. M. AZZARANO, C. A. EVANS and B. R. SMITH

Preclinical Drug Discovery, Cardiovascular & Urogenital Center of Excellence in Drug

Discovery, GlaxoSmithKline, King of Prussia, PA 19406, USA

2. xenobiotica, april 2004, vol. 34, no. 4, 367-377

Apparent absolute oral bioavailability in excess of 100% for a vitronectin receptor antagonist (SB-265123) in rat. II. Studies implicating transporter-mediated intestinal secretion

Dear Andrea,

The following links contain publications which list the bioavailable concentrations of different cations and anions, particularly, Ca, Mg, K and P ions:

Hoping this will be helpful,

Rafik

You may use them, but you should check for TEER and expression of ABC-transporters, e,g, by Western blotting.

Dear Viviana,

For in vitro models of the BBB, please see the following links which contain contact addresses of companies making such service:

1-For this need Across Barriers has established and standardized an in vitro model of the blood-brain-barrier which is based on cerebral capillary endothelial cells.

2-Flocel’s in vitro BBB Model

3-PAMPA

Blood-Brain Barrier Permeability CNS Screening of candidate drug molecules is done using a PAMPA assay to model blood-brain barrier (BBB) permeability. Rodent in vivo and in situ studies of the kinetics of drug uptake across the BBB are valuable tools for assessing factors important to steady-state brain penetration. These are relatively expensive and time consuming assays to do, and are done only sparingly. Animal studies can be augmented by PAMPA, which for BBB uses a mixture of phospholipids infused into lipophilic microfilters, with net negative lipid charge, a system mimicking many of the properties of brain lipid membranes. The data is used to predict brain uptake kinetics, as indicated by PS values determined by in situ perfusion methods

Hoping this will be helpful,

Rafik

Dear Teena,

There are four drug products, Sandimmune and Sandimmun Neoral (cyclosporin A), Norvir (ritonavir), and Fortovase (saquinavir) on the pharmaceutical market, the active compounds of which have been formulated into specific Self-emulsifying drug delivery systems (SEDDS).

For more on this topic you can see the following publications:

1-Biomed Pharmacother. 2004 Apr;58(3):173-82.

Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs.

Gursoy RN1, Benita S.

The oral delivery of hydrophobic drugs presents a major challenge because of the low aqueous solubility of such compounds. Self-emulsifying drug delivery systems (SEDDS), which are isotropic mixtures of oils, surfactants, solvents and co-solvents/surfactants, can be used for the design of formulations in order to improve the oral absorption of highly lipophilic drug compounds. SEDDS can be orally administered in soft or hard gelatin capsules and form fine relatively stable oil-in-water (o/w) emulsions upon aqueous dilution owing to the gentle agitation of the gastrointestinal fluids. The efficiency of oral absorption of the drug compound from the SEDDS depends on many formulation-related parameters, such as surfactant concentration, oil/surfactant ratio, polarity of the emulsion, droplet size and charge, all of which in essence determine the self-emulsification ability. Thus, only very specific pharmaceutical excipient combinations will lead to efficient self-emulsifying systems. Although many studies have been carried out, there are few drug products on the pharmaceutical market formulated as SEDDS confirming the difficulty of formulating hydrophobic drug compounds into such formulations. At present, there are four drug products, Sandimmune and Sandimmun Neoral (cyclosporin A), Norvir (ritonavir), and Fortovase (saquinavir) on the pharmaceutical market, the active compounds of which have been formulated into specific SEDDS. Significant improvement in the oral bioavailability of these drug compounds has been demonstrated for each case. The fact that almost 40% of the new drug compounds are hydrophobic in nature implies that studies with SEDDS will continue, and more drug compounds formulated as SEDDS will reach the pharmaceutical market in the future.

2-Crit Rev Ther Drug Carrier Syst. 2009;26(5):427-521.

Self-emulsifying drug delivery systems (SEDDS): formulation development, characterization, and applications.

Singh B1, Bandopadhyay S, Kapil R, Singh R, Katare O.

Author information

 

Self-emulsifying drug delivery systems (SEDDS) possess unparalleled potential in improving oral bioavailability of poorly water-soluble drugs. Following their oral administration, these systems rapidly disperse in gastrointestinal fluids, yielding micro- or nanoemulsions containing the solubilized drug. Owing to its miniscule globule size, the micro/nanoemulsifed drug can easily be absorbed through lymphatic pathways, bypassing the hepatic first-pass effect. We present an exhaustive and updated account of numerous literature reports and patents on diverse types of self-emulsifying drug formulations, with emphasis on their formulation, characterization, and systematic optimization strategies. Recent advancements in various methodologies employed to characterize their globule size and shape, ability to encapsulate the drug, gastrointestinal and thermodynamic stability, rheological characteristics, and so forth, are discussed comprehensively to guide the formula-tor in preparing an effective and robust SEDDS formulation. Also, this exhaustive review offers an explicit discussion on vital applications of the SEDDS in bioavailability enhancement of various drugs, outlining an overview on myriad in vitro, in situ, and ex vivo techniques to assess the absorption and/ or permeation potential of drugs incorporated in the SEDDS in animal and cell line models, and the subsequent absorption pathways followed by them. In short, the current article furnishes an updated compilation of wide-ranging information on all the requisite vistas of the self-emulsifying formulations, thus paving the way for accelerated progress into the SEDDS application in pharmaceutical research.

 http://www.ncbi.nlm.nih.gov/pubmed/20136631

3-http://www.ijddr.in/drug-development/self-emulsifying-drug-delivery-system-a-conventional-andalternative-appproach-to-improve-oral-bioavailability-oflipophilic-drugs.php?aid=5486

4-Development and Evaluation of Liquid and Solid Self-Emulsifying Drug Delivery Systems for Atorvastatin

Anna Czajkowska-Ko´snik 1,*, Marta Szekalska 1 , Aleksandra Amelian 1,2, Emilia Szyma ´nska 1 and Katarzyna Winnicka

Abstract: The objective of this work was to design and characterize liquid and solid self-emulsifying drug delivery systems (SEDDS) for poorly soluble atorvastatin. To optimize the composition of liquid atorvastatin-SEDDS, solubility tests, pseudoternary phase diagrams, emulsification studies and other in vitro examinations (thermodynamic stability, droplet size and zeta potential analysis)

were performed. Due to the disadvantages of liquid SEDDS (few choices for dosage forms, low stability and portability during the manufacturing process), attempts were also made to obtain solid SEDDS. Solid SEDDS were successfully obtained using the spray drying technique from two optimized liquid formulations, CF3 and OF2. Despite liquid SEDDS formulation, CF3 was characterized by lower turbidity, higher percentage transmittance and better self-emulsifying

properties, and based on the in vitro dissolution study it can be concluded that better solubilization properties were exhibited by solid formulation OF2. Overall, the studies demonstrated the possibility of formulating liquid and solid SEEDS as promising carriers of atorvastatin. SEDDS, with their unique solubilization properties, provide the opportunity to deliver lipophilic drugs to the gastrointestinal tract in a solubilized state, avoiding dissolution—a restricting factor in absorption

rate of BCS Class 2 drugs, including atorvastatin.

5- ISRN Pharmaceutics

Volume 2013 (2013), Article ID 848043, 16 pages

Review Article

Formulation Strategies to Improve the Bioavailability of Poorly Absorbed Drugs with Special Emphasis on Self-Emulsifying Systems

Shweta Gupta,1 Rajesh Kesarla,1 and Abdelwahab Omri2-

Abstract

Poorly water-soluble drug candidates are becoming more prevalent. It has been estimated that approximately 60–70% of the drug molecules are insufficiently soluble in aqueous media and/or have very low permeability to allow for their adequate and reproducible absorption from the gastrointestinal tract (GIT) following oral administration. Formulation scientists have to adopt various strategies to enhance their absorption. Lipidic formulations are found to be a promising approach to combat the challenges. In this review article, potential advantages and drawbacks of various conventional techniques and the newer approaches specifically the self-emulsifying systems are discussed. Various components of the self-emulsifying systems and their selection criteria are critically reviewed. The attempts of various scientists to transform the liquid self-emulsifying drug delivery systems (SEDDS) to solid-SEDDS by adsorption, spray drying, lyophilization, melt granulation, extrusion, and so forth to formulate various dosage forms like self emulsifying capsules, tablets, controlled release pellets, beads, microspheres, nanoparticles, suppositories, implants, and so forth have also been included. Formulation of SEDDS is a potential strategy to deliver new drug molecules with enhanced bioavailability mostly exhibiting poor aqueous solubility. The self-emulsifying system offers various advantages over other drug delivery systems having potential to solve various problems associated with drugs of all the classes of biopharmaceutical classification system (BCS).

6-Acta Pharm. 62 (2012) 563–580 Original research paper

DOI: 10.2478/v10007-012-0031-0

Formulation development of an albendazole self-emulsifying drug delivery system (SEDDS) with enhanced systemic exposure

The aim of the study was to develop and evaluate a self--emulsifying drug delivery system (SEDDS) formulation to improve solubility and dissolution and to enhance systemic exposure of a BCS class II anthelmetic drug, albendazole (ABZ). In the present study, solubility of ABZ was determined in various oils, surfactants and co-surfactants to identify the microemulsion components. Pseudoternary phase diagrams were plotted to identify the microemulsification existence area. SEDDS formulation of ABZ was prepared using oil (Labrafac Lipopfile WL1349) and a surfactant/co-surfactant (Tween 80/PEG 400) mixture and was characterized by appropriate studies, viz., microemulsifying properties, droplet size measurement, in vitro dissolution, etc. Finally, PK of the ABZ SEDDS formulation was performed on rats in parallel with suspension formulation. It was concluded that the SEDDS formulation approach can be used to improve the dissolution and systemic

exposure of poorly water-soluble drugs such as ABZ.

Hoping this will be helpful,

Rafik

Dear Richard,

The following recent review entitled "Toxicity of Engineered Nanoparticles in the Environment " by Melissa A et al. published in Anal Chem. 2013 Mar 19; 85(6): 3036–3049 devotes a section on multicellular aquatic and terrestrial organisms and the delivery pathways of toxic materials:

While nanoparticles occur naturally in the environment and have been intentionally used for centuries, the production and use of engineered nanoparticles has seen a recent spike, which makes environmental release almost certain. Therefore, recent efforts to characterize the toxicity of engineered nanoparticles have focused on the environmental implications, including exploration of toxicity to organisms from wide-ranging parts of the ecosystem food webs. Herein, we summarize the current understanding of toxicity of engineered nanoparticles to representatives of various trophic levels, including bacteria, plants, and multicellular aquatic/terrestrial organisms, to highlight important challenges within the field of econanotoxicity, challenges that analytical chemists are expertly poised to address.

Hoping this will be helpful,

Rafik

Dear Ghfran,

Lead (Pb) is an element present in the environment that negatively affects all living organisms. To diminish its high toxicity, micro-organisms have developed several mechanisms that allow them to survive exposure to Pb(II). The main mechanisms of lead resistance involve adsorption by extracellular polysaccharides, cell exclusion, sequestration as insoluble phosphates, and ion efflux to the cell exterior. T

Lead precipitation in the form of lead phosphate results in avoiding re-entry of lead into the cells.

For a recent review on this topic please use the following link:

Lead resistance in micro-organisms

Anna Jarosławiecka and Zofia Piotrowska-Seget

Microbiology (2014), 160, 12–25

 Hoping this will be helpful,

Rafik

Here are two useful pdf attachments for your persual.

Dear Roghayeh Vahedi,

Long-term effects of biochar on nutrients occur through complex physiochemical reactions with soil particles (Spokas et al., 2011). One such reaction that affects

P is biochar-induced increases in soil alkalinity (liming). In acidic soils phosphorus can be adsorbed onto iron oxides, which makes it unavailable to plants. Liming agents

reduce the concentration of iron and aluminum in the soil solution and the previously bound phosphorus then becomes available (Cui et al., 2011).

Spokas KA, Cantrell KB, Novak JM et al. (2011) Biochar: synthesis of its agronomic

impact beyond carbon sequestration. Journal of Environmental Quality, 41, 973–989.

Cui H-J, Wang MK, Fu M-K, Ci E (2011) Enhancing phosphorus availability in phosphorus-fertilized

zones by reducing phosphate adsorbed on ferrihydrite using

rice straw-derived biochar. Journal Soils Sediments, 11, 1135–1141

For more details, please use the follow link which contains a review article which covers this topic:

Hoping this will be helpful,

Rafik

Dear Santi,

If a drug is not soluble in water or has a very low solubility it can not be absorbed through the membranes and thus its permeability will be negligible and consequently its bioavailability will be too low.

In addition if a drug is too hydrophilic (such as salts) with very low log P value ( -6 or lower), the drug will not be absorbed through membranes since for permeation to occur the drug should have a moderate HLB (hydrophilic lipophilic balance) value, Thus resulting in low permeation  and very poor bioavailability .

To achieve a high bioavailability, the drug should be soluble in water and have a moderate HLB value in order to permeate through membranes.

Fick's low (passive diffusion); drugs are transferred (diffused) from high concentrations to low concentration and the rate of diffusion is linearly correlated with the difference in the concentrations of the drug outside and inside the membrane and its inversely correlated with the membrane thickness. Therefore, Fick's low is related to drugs permeation.

Example: glibenclamide, bicalutamide, ezetimibe, phenytoin, aceclofenac

The bioavailability of those products is limited by their solvation rate. A correlation between the in vivo bioavailability and the in vitro solvation can be found.

The compounds in this class have poor water solubility. For a drug to be absorbed or diffused through membranes (intestine) it firstly has to be dissolved in the physiological medium. Since these drugs are not soluble in the physiological media they can not be absorbed thus resulting in poor bioavailability.

For permeation to occur, the drug should first be dissolved. Therefore, although these drugs have very good permeation they can not be transported due to their poor solubility in aqueous medium.

Hoping this will be helpful,

Rafik