Pharmacokinetics - Science topic

Jagtar Singh So i will apply population PK not non-population PK study, Is it right ?

Do you want to include in the model some interactions between the drugs. Are they impactinh each other's PK?

If not and you simply want to model the 3 drugs on its own it may be easier to model each seprately. You could also write a model with distinct parameters names for each drug, but this may become uneccesarily complictaed.

Dear Colleague,

I hope this message finds you well. Understanding the pharmacokinetic (PK) differences between rats and mice is essential for interpreting preclinical data and translating findings to human applications. Several factors contribute to these differences, which I detail below:

In conclusion, multiple factors, including metabolic rate, enzyme expression, absorption, distribution, excretion, physiological and anatomical differences, genetic factors, and experimental conditions, contribute to the pharmacokinetic differences observed between rats and mice. Careful consideration and control of these factors are essential for accurate interpretation and comparison of PK data across species.

Should you have any further questions or require additional assistance, please feel free to reach out.

What factors may contribute to the PK differences in rats and mice?

After oral administration, olanzapine is rapidly absorbed, reaching peak plasma concentrations within 5 to 8 hours. It has a high bioavailability of roughly 60%, with meals slightly slowing absorption. Olanzapine binds to plasma proteins and distributes throughout the body, including passing the blood-brain barrier to affect the central nervous system. Metabolism occurs largely in the liver via the cytochrome P450 system, specifically CYP1A2 and CYP2D6 enzymes, producing a variety of metabolites, including the active metabolite N-desmethylolanzapine. Then, elimination is predominantly accomplished through hepatic metabolism and subsequent renal excretion of metabolites, with a half-life of around 30 hours.Patients with hepatic or renal impairment may require dosage changes due to changed pharmacokinetics.

Pharmacokinetic and pharmacodynamic changes occur during pregnancy, impacting drug metabolism, distribution, and response in pregnant patients. Understanding these changes is crucial for safe and effective medication management during pregnancy. Here's an overview of the key alterations:

In summary, pharmacokinetic and pharmacodynamic changes during pregnancy can influence drug metabolism, distribution, and response, posing challenges for medication management in pregnant patients. Clinicians must consider these alterations when prescribing medications, adjusting dosages, and monitoring therapeutic effects to optimize maternal and fetal outcomes while minimizing risks of adverse drug reactions. Close collaboration between obstetricians, anaesthesiologists, and pharmacists is essential for safe and effective medication use during pregnancy.

During pregnancy, significant physiological changes occur to support fetal development and accommodate the needs of both the mother and the growing fetus. These changes have implications for anaesthesia management and can impact various organ systems and pharmacokinetics. Here's an explanation of some key physiological changes and their implications for anaesthesia:

In summary, the physiological changes that occur during pregnancy have significant implications for anaesthesia management, affecting cardiovascular, respiratory, renal, gastrointestinal, and hormonal systems. An understanding of these changes is essential for anaesthesia providers to optimize maternal and fetal outcomes and minimize perioperative complications in pregnant patients undergoing surgery or obstetric procedures. Close monitoring, individualized care, and multidisciplinary collaboration are key components of safe and effective anaesthesia management during pregnancy.

Hi,

If you are a University scientist try to ask Lixoft about PKanalix availability (academic license) ..... easy intuitive soft (https://lixoft.com/).

I also recommend their spring school (every year PK training program online, free of charge).

Best regards,

Tomasz

Dear friend Jake Ellis-Williams

Alright, let's tackle this like I would!

Designing a pharmacokinetic study for a new CNS drug, eh? Now, we're talking real science. First things first, if you Jake Ellis-Williams don't have any toxicology data, you're in a bit of a tight spot. But I dont shy away from challenges!

1. **Start Low, Go Slow:**

- In the absence of toxicology data, the golden rule is to start low. You Jake Ellis-Williams don't want to accidentally turn your rats into rocket ships, do you? Use a dose that's unlikely to cause adverse effects.

2. **Reference Similar Compounds:**

- Check out similar drugs in the antidepressant family. It's not a perfect science, but it gives you Jake Ellis-Williams a ballpark figure. Look at the literature, see what doses they used, and take a leap from there.

3. **Consider Route of Administration:**

- Are you Jake Ellis-Williams going oral or intravenous? Oral is more common, but if you're feeling adventurous, go IV. Adjust your dose accordingly; IV doses are typically lower due to higher bioavailability.

4. **Species Matters:**

- Rats are not humans. Shocking, I know. Their metabolism differs, so don't just scale up a human dose. Consider allometric scaling, a fancy term for adjusting doses based on body surface area.

5. **Monitor Behavior:**

- Keep a close eye on your rats. If they start tap-dancing or speaking French, you Jake Ellis-Williams might have gone a bit too high. Watch for signs of toxicity and adjust your doses accordingly.

6. **Pilot Studies are Your Friends:**

- Before diving into the big show, run some pilot studies. Test the waters with a few rats. It's like a movie trailer – gives you Jake Ellis-Williams a taste without committing to the full feature.

7. **Consult the Oracle (Experienced Scientists):**

- If you Jake Ellis-Williams have access to seasoned scientists, consult them. They've been around the block and can provide invaluable insights. Wisdom often comes with gray hair and lab coats.

8. **Ethics Committee Approval:**

- Don't forget to run your doses past the ethics committee. They might not have a Ph.D., but they know a thing or two about keeping experiments humane.

Remember, my science-seeking friend, this isn't a one-size-fits-all scenario. The key is to be cautious, use your scientific instincts, and be ready to adapt as your data rolls in. May the pharmacokinetics odds be ever in your favor!

The abstract of the paper you mention states:

So, in the picture, you provided ANS9801 is equivalent to Advantame (if we omit the water molecule included in Advantame). But the paper clearly mentions ANS9801-acid, that indicates the structure of ANS9801 without methyl ester functionality (which has been hydrolyzed to free acid, meaning that ANS9801-acid has, in fact, two carboxylic groups).

The exact structure is provided and subscribed as ANS9801-acid in Fig.22, showing the proposed metabolic pathway of ANS9801, in the paper you cite.

pkcsm and AdmetSAR are more often applied webservers for evaluating ADME properties, Protox II for toxicity, and swissADME for drug-likeness properties. If you have access to Schrodinger software, it will be better to use Quikprop so as to evaluate the pharmacokinetic properties comprehensively.

Try discus the topic with Lixoft they have amazing software and free of charge academic version probably is a possible option. Link below:

Hi Jagtar, it would depend on what is the lower limit of quantification of your analytical method and subsequently how much blood you need per sampling time point. Generally for a 25 g mouse the recommendation is not more than 250uL blood in 24h period. I would recommend that if you need 250uL per time point (around 5 drops) then you could make groups of 3-5 mice for each time point. ie. dose 18-45 mice. Alternatively to reduce the number of mice in the study, you could refer literature available for the drug and reduce your timepoints.

BUT THIS JOURNAL IS TAKING CHARGE/FEE FOR PUBLISHING ARTICLE.

PLEASE SUGGEST REPUTED JOURNAL WHICH WILL NOT TAKE CHARGE.

yes i worked two times but this model not properly works in excel.This model given my senior.After i used other software.

Dear Murugesan Arumugam,

Pl refer link (page 22-23) for calculation of loading and maintenance dose based on PK parameters.

Regards

Hitesh Chavda

David Salehi Thank you for your recommendations. I will certainly have a look at them.

based on a double-blind, multicenter, RCT comparing 1,000 mg tabs vs 500 mg tabs (same daily dose) in acute hemorrhoid, the authors concluded that "We have been demonstrated that the new single MPFF 1000 mg tablet has clinical acceptability and a good safety profile, comparable to that of MPFF 500 mg tablets. MPFF 1000 mg was as effective as MPFF 500 mg in reducing anal pain and bleeding. The new dose regimen should lead to better treatment adherence and consequently to better management of hemorrhoidal disease."

Hi,

Sounds like a basic question but is very often asked by experienced scientists. The answer is it depends on your goal. Measurement PK does not always mean analysis 'only' PK so the dose will be different if:

And many others factors and goals may change decisions about dose amount. But one critical is a range of validation of your analytical method. If for example, LLOQ of your method is 10 ng/mL you can't use a dose that gives concentrations between 0.01-3.0 ng/mL. Consequently in your PK study:

Please remember that the calculation is very very general because depending on study item many processes may change this value within seconds (blood protein binding, first-pass effect, route of administration, and presence of absorption phase etc). So if possible always if you have no data which can be translated from other animals or homologs try to make a pilot study it is always very helpful for both optimizations of the analytical method and dose level. The pilot could be done only with a few animals and a few samples of blood.

Some useful tips related to single-dose PK you can find in my paper below:

Best regards

Tomasz

Hi, how about this site?

NCA: http://nca.kscpt.org/

Compartment modeling: http://ca.kscpt.org/

I guess when concentration becomes too low, you might have to look for cues like calibration of the detector, and other variables such as temperature and pressure which affect rate of the reaction. Solubility and saturation might also be considerations. A slow reaction might take a longer period of time to measure.

Hi,

The best way for sampling from small animals is the sparse sampling method (if you have no access to cannulated animals + a very sensitive method). In the case of sparse sampling, you can implement the options present in software for example Phoenix WinNonlin (see reference below). Even if you work with very small animals or sparse sampling rules related to PK analysis are in close link with study design and PK curve structure. Those rules are the same like in humans or large animals If its typical single dose study with small population (excluding for example large populations and population PK were sampling is different or therapeutic drug monitoring etc.). Consequently, for example, 7 sampling points per typical single dose, frequent sampling curve in an exploratory study is not folowing the rules. Descriptiion of expectations related to typical frequent sampling in single dose PK studies (not population methods of analysis) you can find in my paper which shows some compilation of current consensus both in science and regulatory trials.

These are the principles that follow the principles of analytical geometry & mathematics. It is the common denominator of these rules. If you follow these rules, you will exclude any BIAS resulting from the lack of an optimized sampling design. The last rule about Clast Cmax will prevent you from calculating an elimination rate constant based on distribution phase rather than elimination. For example, if your expected Cmax is 100 ng/mL your analytical method LLOQ should be around 1 ng/mL rather than 10-15 ng/mL. If you follow these rules, you will always be on the safe side. To implement them, the best solution is a pilot analysis with a few animals before starting the main study and a validated sensitive method of analysis.

Hope this comment could be useful,

Best regards

Tomasz

Sparse sampling reference: https://onlinehelp.certara.com/phoenix/8.3/topics/Sparse_sampling_calculation.htm

.

Dear Sherouk,

Another thought I had is that you may be able to study the correlation differently.

Is the biomarker expected to change very rapidly in response to drug? Is this why you want to correlate to Cmax? Is it also going to be itself eliminated very quickly when drug concentrations decrease?

If these conditions are met you could try to fit an Emax / Imax model to the data (biomarker as a function of drug concentration at any time).

For this to makes sense you would need the biomarker to have a fast turnaround (faster than drug kinetics) and to show fast response to drug.

Respected Prof Faraz Khurshid , I cannot agree with you more. I think PD/PK are really subjects that needs to be emphasized in modern pharmacy training. We really need fundamental and basic scientific training for every pharmacist. Scientific concept is important for clinicians.

I also like evidence-based medicine, I guess this is really an important direction for our future generations. It is the black and white evidence that really underlie our decision and we should record the evidence accordingly so that we are speaking the same language and sharing our knowledge.

It is important that every decision is recorded and traceable, so that we are recognized as a professional and/or expert in a particular area(s).

Hi Manikandan. Interesting exercise. Kindly see the attached workout. I hope it will guide your further efforts on the assignment.

In summary, it appears from the first table that:

1. Compounds 2 and 3 exhibit lower clearance, and higher bioavailability.

2. Compared to Compounds 1 and 5 (which exhibit equipotency), Compounds 2, 3, and 4 exhibit lower potency, Compound 2 much less so than the others.

3. Compound 4 exhibits lower bioavailability, a lower Cmax and, higher clearance.

4. Compound 5 exhibits the lowest Cmax but with unknown bioavailability and clearance. Safe to assume a high Vd and thus high clearance from the central compartment, and low bioavailability.

Dear Siam,

I'm afraid I haven't come across allometry for such cases. In general allometry is used to scale between mammalian species (or individual of different sizes for pediatric applications).

The general idea is that flows (clearance) scales with a factor of about 0.75, so this applies also to dose (which is expected to be a function of clearance). So it follows a relationship of a*BW^0.75.

In absolute terms you could apply the formula with the weight of any species / individual. However, I suspect that the empirical principles mainly established between mammals may not apply to invertebrates.

To note that even between more similar species like mammals allometry does not always work well.

Out of curiosity, how do you apply drugs in insects? Can you actually apply orally or how it it done?

The words selectivity, specificity, and sensitivity (derived from Latin seligere, specificus, sensitivus), can be confusing terms as they are often used synonymously in the medical literature. However, they should not be used

interchangeably as each represents a different phenomenon.

Reference:

Mencher, S. K., & Wang, L. G. (2005). Promiscuous drugs compared to selective drugs (promiscuity can be a virtue). BMC clinical pharmacology, 5(1), 1-7.

many thanks doctors for your response..

would you recommend any supporting articles for this area of study Falguni Manoj Saraswat Tohlang Sehloho

This paper could address the issue:

There are many iso enzymes that metabolism drug ,not necessarily the both Niacin and statin have same iso enzyme.

Important other important factor is the dose of Niacin may be very low to elicit metaboliic process.

@karel

I wish to know if there's any genetic polymorphism/variation in the pharmacology of frusemide. Whether at the level of safety, pk or pd?

Is there anything of concern in this regard sir?

Hi Ashish,

You can do NCA analysis of all derived data if you have a full profile in organs.

Additionally from tissue data, you can derive tissue to plasma ratio. It will help you in understanding the drug disposition in various tissue.

From the CT profile of the animal, you can extrapolate the various doses and dose regimens by compartmental analysis. if you have sufficient subject then you can derive information about covariate impact on PK by popPK.

if you need further assistance let me know.

That makes sense. Could you be referring to C0 instead of Cmax instead? C0 is the extrapolated value to time 0, which will be Dose/Vd. If C0 changed and your dosing is constant, it is likely that there was a difference in volume of distribution that occurred. I generally find Vd harder to explain biologically as the reason for the change could be anything from changed transporters in blood cells to fat or other peripheral tissues or plasma protein binding.

In IV data, Ke = CL/Vd. If CL changed, but Ke did not, it is possible that Vd also changed to similar extent. Ke = ln2/(t1/2), so if Ke does not change, t1/2 will not change. An easy way to see this would be (as a quick and dirty way of ensuring your calculations were correct), if you plot your plasma data on a log 10 y axis, do the gradients of each mouse group look similar? Ke is pretty much the slope on that graph. Here is a list of useful PK equations that I often reference to understand such plots better. https://pharmacy.ufl.edu/files/2013/01/5127-28-equations.pdf

It is also possible that the virus you were administering did not do what you expected. Perhaps other things to investigate post sac, e.g. kidney histology - did the virus damage the kidney tissue?

Thank You Riaz & Tejas

Hi,

Unfortunately, there are no such methods. Current solutions and models do not allow for selective analysis of one or several substances after administering the extract (.... which may contain several substances). Such analysis will only inform about interactions between constituents nothing else. Of course, the extent of these PK interactions will depend on the composition of the extract. What you can do is determine the concentration of the dominant substance in the extract and try to determine its concentration in blood samples or urine. However, the cognitive and scientific value of such an analysis will still be low. If an extract is administered, it is not possible to associate a single substance with a pharmacodynamic effect (PD). Currently, we do not have such data analysis capabilities. The effect of PD after administration of the extract is always the result of interactions between all components of the extract. We currently have neither software nor models that can separate these interactions from each other. Therefore, PK and PD are tested with the use of single selected substances or in systems where interactions with one substance are tested, but not with so many.

All you can do is try to characterize the chemical composition of the extract and describe/analyze the PD effect. Selective analysis of PK or selective PD analysis in your case is not possible.

Best regards

Tomasz

Hi

There could be many reasons why you do not see typical absorption phase after oral administration in your PK profile for example:

Best regards

Tomasz

Arthur Saus I agree with you

Interpolation can be thought of in two ways:

1) Interpolation methods approximate some underlying model

2) Interpolation simply approximates a set of numbers continuously

In case 1), interpolating will capture the essence of the underlying function, if and only if, the data is representative of the fundamental model. Noise will definitely throw your results off.

In case 2), you are simply generating an approximation from a set of known numbers, e.g. Lagrange interpolation; forward, centered and backward Newtonian interpolation, &c. The numbers in hand may or may not represent anything in particular, or, they may not be accurate enough to enable one to gleam the underlying processes. Purely interpolated results can and do grow wild as the power of interpolation is increased.

What I suggest is a low power interpolation of the database, then look at the curve and compare to any model you have in mind. If the interpolated results resemble strongly enough some model, then you may further pursue investigating along that vein.

Hi

"enantioselective pharmacokinetics" please check the keyword in google or NCBI.

geometrical isomers have different physicochemical characteristics for example pKa, the same problem cover diastereoisomers.

D-dopa is less absorbed than L-dopa

D-methotrexate is less absorbed than L-methotrexate

cis - lycopene is absorbed to a greater extent than trans - lycopene

L - cephalexin inhibits the absorption of D - cephalexin from the gut

R-methadone has a greater volume of distribution than S-methadone

R - (-) - disopyramide binds less to blood proteins than S - (+) - disopyramide

Cis-cis - mivacurium has a larger volume of distribution than cis-trans, trans-trans

S - propranolol binds more strongly (competes) with plasma proteins than R - propranolol

R - sulbenicillin binds to plasma proteins weaker than S - sulbenicillin

R - latamoxsef binds to plasma proteins more strongly than S - latamoxsef

R-carbenicillin binds to plasma proteins more strongly than S-carbenicillin

R - propafenone delays the metabolism of S - propafenone

S - nitrendipine is an inhibitor of R - nitrendipine metabolism

R - verapamil is less affected by the first-transition effect than S - verapamil

R - ketoprofen in most species is transformed into S ketoprofen (rodent, dog, monkey, horse, cat) the Asian elephant is the only species that converts S into R

A very interesting case is a chiral inversion in the liver (see examples below)

flobufen (Skalova L. et al 2001)

ibuprofen (Doki K. et al 2003)

pranoprofen (Imai T. et al. 2003)

ketoprofen (Lees P. et al. 2003)

fenoprofen (San Martin M.F. et al. 2002)

albendazole (Virkel G. et al 2002)

thalidomide (Erikson T. et al. 2001)

clopidogrel (Reist M. et al. 2000)

D-leucine (Hasegava H. et al. 2000)

thiaprofenic acid (Erb K. et al 1999)

pantoprazole (Masubuchi N. et al. 1998)

styripentol (Tang C. et al. 1994)

lifibrol (Walters R.R. et al. 1994)

Tolperizon (Yokoyama T. et al. 1992)

R-methadone has a longer half-life than S-methadone

R-ibuprofen has a shorter half-life than S-ibuprofen

(-) - mefloquine has a longer half-life than (+) - mefloquine

R - (-) - ketamine inhibits the elimination of S - (+) - ketamine

(+) - terbutaline inhibits tubular reabsorption of (-) - terbutaline

R - sotalolol reduces the renal clearance of S - sotalolol

R - flurbiprofen is excreted from the bile to a greater extent than S - flurbiprofen

R - carprofen is secreted from the bile to a greater extent than S - carprofen

R - sulbenicillin has a lower renal clearance than S - sulbenicillin

R - (+) - propranolol is eliminated more slowly than S - (+) - propranolol

Z - doxepin has a stronger antidepressant effect than E - doxepin

Z - doxepin has a stronger antidepressant effect than E - doxepin

S (-) bupivacaine is less toxic than racemic bupivacaine

Of course, it's only the peak of the iceberg so, please check:

.... now > 1000 results ....

examples with references are available in my free e-book (polish version only)

Best regards

Tomasz

In addition to the answer of Geertje you should carefully purge the vascular system by perfusion of saline or an appropriate buffer

best regards , Gert

You can use the device for PCcaps Capsules, which is designed for rats.

it depends on your hypothesis, how big do you anticipate a difference will be ? this difference should at best be of clinical relevance, so that if the study is negative, that we have learned that this covariate is not of clinical relevance ?

Many thanks @ Simon AA Davis

Hello,

The best software isn't free. It's expensive. You can try the PKMP trial version https://aplanalyst.com.

Hello Anna,

Lots of thanks for the response and the link was very helpful.

I am grateful indeed.

Hi

Conclusion about no interactions probably cover lack of meaningful PD observations see:

" Candesartan cilexetil produced a 7% decrease in trough plasma warfarin concentration but this had no effect on prothrombin time. "

So in some cases pharmacokinetic interaction can exist but have no impact on clinical findings. Probably this is why you find conclusions about lack of interaction. Finally protein binding in blood plasma not must be most important aspect of interactions between both drugs

from another hand:

" Candesartan had no effect on S-warfarin 7-hydroxylation. In contrast, S-warfarin inhibited candesartan metabolism by the wild-type (K = 17microM) greater than by the Leu359 variant (Ki = 36 microM). These findings suggest that CYP2C9*3 may change not only the metabolic activity but also the inhibitory susceptibility compared with CYP2C9*1. "

Best regards

Tomasz

Hi

To be onest from my point of view best are FDA documents related to specific drug submission its better than any database (for example drugbank https://go.drugbank.com/drugs/DB00341) ....

for example

google, key words: fda cetirizine pharmacokinetics accedata

Or maybe such books will be better

Best regards

Tomasz

Hi,

You can't predict or simulate S.C. pharmacokinetics without knowledge about bioavailability after S.C. administration in vivo. After you have this information you can simulate or calculate „treatment” – multiple-dose experiments. If you have no flip-flop effects or no issues with non-linear PK then sampling intervals after S.C. should be more less in the same range (zero-last sampling point) as in IV. So planing S.C. should not be very complicated. Of course, you should use some let say general rules for sampling optimization in singe dose studies. See the table 2 from my paper below. Should be useful.

Best regards

Tomasz

Please bear in mind that there is a large interindividual variability in the bioavailability and therefore the plasma concentration of parent mycophenolate and active metabolite. The variation can b as large as 30%. You may consider checking the plasma concentration in critical cases.

Hi

Please try sparse sampling method. For example for one time point you can take single sample from 1-3 different rats (rat number 1, 2, 3) for next point single sample from 3 next rats (rat number 4, 5, 6). You can reduce number of animals and leave them alive.

Examples how software can solve such set of data in NCA PK:

Example of study design:

I hope this helps you .... and your rats as well :-)

Best regards

Tomasz

Yes. I did.

To establish the calibration curve in a matrix similar to your unknown samples, in this case your matrix is plasma, is considered the best option to account for matrix interference with your analytes of interest. It is known as "Matrix-Matched Calibration". It is a common practice when you expect an intereference that may decrease or increase the analytes' signal in the Mass Spectrometer.

To establish the calibration curve in a matrix similar to your unknown samples, in this case your matrix is plasma, is considered the best option to account for matrix interference with your analytes of interest. It is known as "Matrix-Matched Calibration". It is a common practice when you expect an interference that may decrease or increase the analytes' signal in the Mass Spectrometer.

Thus, to answer your question in simple words, yes it is necessary, at least from analytical point of view.

You may refer to some publications about matrix effect in mass spectrometry, like on of my papers in my profile.

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

Dear Goutam Kumar Jena

As previously mentioned by Siddhartha Dutta

I proposed that the http://www.swissadme.ch/ is the best choice

All the best

Por su puesto esto depende de la Biodisponibilidad de cada sustancia y las condiciones de su administración y eliminación. Lo más importante es como afecta la Seguridad y la Eficacia en Terapéutica

Michaelis–Menten kinetics is one of the best known models of enzyme kinetics in in vitro drug elimination or drug-drug interaction experiments. it consists of two parameters, the maximum reaction rate (Vmax) and the Michaelis constant (Km) describing the rate of enzymatic reactions by relating reaction rate (V) to the concentration of a substrate ([S]). By definition, Km is equal to the concentration of the substrate at half Vmax. It can also be thought of as a measure of how well a substrate complexes with a given enzyme, otherwise known as its binding affinity. An equation with a low Km value indicates a large binding affinity, as the reaction will approach Vmax more rapidly.

Go forAlamar Blue assay that does not require lysis at all.

The publications of Peter Meier describing isolation of hepatic membrane vesicles may be helpful. e.g. J Cell Biol. 1984 Mar;98(3):991-1000.

Hi Andy,

Link works correctly but if not in your PC then try with phrase "boomer pk course" in google.com and click first link from the top,

Best regards

Tomasz

Dear Tejosmita Sen

Few points should be useful I hope:

- develop bioanalytical method for your molecule determination in blood plasma (or blood plasma and whole blood after hemolysis) without a method you cant do your PK study. Moreover you cant make next steps.

- check ex vivo using blank full blood cell fraction and blood plasma, or hemolysed full blood (frozen blood) does your molecule transfer to RBC or not (then you will know what analytical matrix will be useful for you.)

- Calculate LogP of your molecule. If its lipophilic structure with LogP more less >1 then please remember how big impact it could have for binding with plasma proteins (recovery of your analytical method), affinity for other proteins for example with enzyme activity (CYP) (first pass effect possible).

- decide about route of administration and local toxicity (local toxicity should be a part other tox studies) If IV is possible its easier route for you, if not IP could be usefull. Please remember after IV take first samples immediately after drug administration for example 30 sec, after drug administration 2 min 5 min 15 min 30 min ...... its most important samples because show close to t0 observed concentrations which can go dawn with very high rate.

- use tox studies for planning dose which could be well tolerated

- check carefully what is available in relation to monologues (NCBI etc.)

- make pilot study using 3 animals and for example three doses. Example 1mg/kg (one animal), 3 mg/kg (one animal), 9 mg/kg (one animal). If its IV from fist take sample after 30 sec, from next after 30 sec and from last after 3 hours. Analyse data and trends for first PK study sampling optimization.

- With first PK mice study my suggestion is applying sparse sampling. and two stage approach if sampling will be to short to cover whole PK.

Best regards

Tomasz

Sperm is typically prevented from exposure to blood - because even a male's own sperm is seen by their immune system as "foreign", leading to the formation of anti-sperm antibodies. This can be a problem in clinical situations such as after testicular trauma, leading to infertility.

As such, I dont think sperm delivery into the bloodstream is practical and although I dont have any specific data on it, I believe the survival of sperm in the blood stream would not be very long. The article you have linked to seems to be suggesting the utility of a sperm delivery system for anti-tumour therapy into the female genital tract (in the lumen, not via the bloodstream) to treat malignancies like endometrial cancer. I couldnt access the full text, so not sure how rigiriusly they have tested this - certainly sounds like an interesting idea!

Dear Georgi,

Looking in vitro studies looks that chitosan persist long time and could pass from mother to daughter cells through several mitotic cycles.

" Many polymers (especially the chitosan) and their nano/microparticles, commonly referred to as biodegradable/biocompatible, have been investigated for drug delivery and other medical purposes; however, the mechanism of their degradation has not been fully elucidated in biological systems. Evidence for their in vitro or in vivo degradation is very limited or conflicting. The FDA has approved some polymers for drug delivery and certain medical applications [5] because their degradation products are deemed to be biocompatible and eliminated from the body. However, once these polymers have formed nanoparticles by crosslinking (either by covalent, ionic or other bonds), it is not known whether those nano/microparticles are entirely biodegradable or biocompatible. "

source:

It looks like we currently don't have enough data to say that chitosan doesn't have deep compartments. If it is transmitted from cell to cell in mitotic cycles, this indicates strong binding to cell structures and a very low level of elimination. It is very likely that some fraction of chitosan may be eliminated very slowly and stay in the body for a long time. Chitosan with more 73% degree of deacetylation is hardly degraded. Highly deacetylated chitosan (over 85%) shows a low degradation index in the aqueous environment and will degrade after a few months. This means that the kinetics of elimination of this fraction is non-linear. It also requires the creation of more complex pharmacokinetics models. Until now such models probably are not described in literature.

Best regards

Tomasz

I believe you need to change some of the solvents used, as as Elena V Romanova said, their RT may be the same or similar to your analyte.

Best of luck.

Dear Naïrouz Benzeggouta

If I correctly understand your question is not about food impact on drug PK but exactly "pharmacokinetics" of food components. Its very interesting question. Of course term "pharmaco" could be used only for drugs not for other substances.

In general food contents take part exactly the same process like drug after per os administration :

Food intake is continuous process, that means substances available in the food are absorbed regularly after meal. In such situation we can talk or describe in scientific manner "kinetics" of some food components (single well defined substance) but not "food pharmacokinetics".

In case of food components is very complicated because many components of food are absorbed in very composite environment from chemical and physiological point of view. Food per se change pH, motility, blood perfusion, and other features of the stomach. That change cover not only stomach but bile ejection and other process influencing absorption every single substance - content of the food. Finally one single meal could deliver millions different substances into gastro-intestinal tract (GIT) which interact between each other in absorption phase and other kinetic (not pharmacokinetic) phases .....

Concluding your question there are many differences between

But in both cases we can explain mechanisms and processes using current tools proposed by pharmacometrics.

Hope it helps

Best regards

Tomasz

Hi Frederick Vinckenbosch , yes, you're right. By solving the equation you get 0.25084 mg/l (by using the original units: 20mg and 84L (from 1.4 L/kg*60kg)) which equals 0.25084 µg/ml or 250.84 ng/ml.

Problem solved, then!

Regards, Luis

I work for Certara who write and support Phoenix WinNonlin;

we also provide lots of training options to get the best from the software.

https://www.certarauniversity.com/learn/course/external/view/elearning/26/100-od-introduction-to-phoenix-winnonlin

Simon.

I have found this tool in the web, I think that it uses the IC of 90% and acceptance criteria of 80-125. Please check.

http://epitools.ausvet.com.au/content.php?page=bioequivalence

Hello Yanfei, it is highly probable that your extract inhibited the metabolizing enzymes for irinotecan. Co-administration of certain agents either induces the metabolizing enzymes (leading to rapid clearance/elimination, decreased duration of action and perhaps therapeutic failure) or inhibits the said enzymes, leading to slow clearance/elimination, increased plasma concentration, increased duration of action and perhaps toxicity.

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You can go through these links:

https://www.sigmaaldrich.com/content/dam/sigma-aldrich/docs/Sigma/Product_Information_Sheet/2/m5391pis.pdf

Scale-up effects on dissolution and bioavailability of propranolol hydrochloride and metoprolol tartrate tablet formulations.

Thank you, Dr. Tomasz and Dr. Patrice.