Sichuan University
Question
Asked 13 February 2014
Is there a way to covert in vivo dose to in vivo concentration, or vice versa?
I was wondering if there's any way of converting an in vivo dose e.g., 3 mg/kg in mouse, into a concentration that can be used in in vitro assays, or vice versa. Appreciate all the inputs.
Most recent answer
Converting an in vivo dose to an in vivo concentration or vice versa is a complex task, primarily due to the dynamic nature of drug distribution, metabolism, and elimination within a living organism. However, there are some pharmacokinetic principles and models that can be applied to estimate this conversion, keeping in mind that these estimates often involve approximations and assumptions.
### Key Concepts and Steps
1. **Volume of Distribution (Vd)**: This is a key parameter in pharmacokinetics. The volume of distribution is a theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration as it is observed in the blood plasma.
- **Formula**: \( Vd = \frac{\text{Amount of drug in the body}}{\text{Plasma drug concentration}} \)
2. **Initial Concentration (C0)**: Immediately after intravenous (IV) administration, the initial concentration can be estimated using the dose and the volume of distribution.
- **Formula**: \( C_0 = \frac{\text{Dose}}{Vd} \)
3. **Dose to Concentration**: For a given dose, you can estimate the initial concentration using the above formula. However, for other routes of administration (like oral), bioavailability and absorption kinetics must also be considered.
4. **Concentration to Dose**: To find the dose from a known concentration, you would typically use the volume of distribution. If you know the desired concentration and the volume of distribution, you can estimate the dose.
- **Formula**: \( \text{Dose} = C \times Vd \)
5. **Accounting for Pharmacokinetics**: Realistically, this conversion is not straightforward due to the complexity of drug kinetics in the body. Factors like metabolism, elimination (half-life), and dynamic distribution in different tissues complicate the conversion.
6. **Model-Based Approaches**: Pharmacokinetic models (like one-compartment or multi-compartment models) can be used to more accurately predict how concentrations change over time following a dose.
### Important Considerations
- **Interindividual Variability**: There's significant variability in how different individuals process medications, so these calculations often provide a general estimate.
- **Drug Properties**: Lipophilicity, protein binding, and other chemical properties of the drug affect distribution and concentration.
- **Route of Administration**: Oral, IV, intramuscular, and other routes have different absorption and bioavailability profiles.
### Conclusion
While it's possible to estimate in vivo concentration from a given dose or vice versa, such estimates are inherently approximate. Detailed pharmacokinetic studies and models are often necessary for more precise conversions, especially for new or less-studied drugs. These calculations should always be approached with caution and within the context of comprehensive pharmacokinetic understanding.
l Take a look at this protocol list; it could assist in understanding and solving the problem.
All Answers (15)
Lonza Bioscience
Yes, you can, the only thing you must know is the molecular weight of the substance (or substances) you are using and the volume of the diluent you are going to employ in the in vitro experiment. That way you can calculate the exact quantity of such substance (in mg, ug etc..) and establish a correlation between in vivo dosage and in vitro treatment. However, for in vitro treatments the employed amount of substance is usually much lower than in vivo.
2 Recommendations
Albert Einstein College of Medicine
Diego, can you provide a concrete example on what you are suggesting. Will appreciate it much.
Rob, your input is very much appreciated.
2 Recommendations
Lonza Bioscience
Sure.
Imagine that the substance you are using is for example, NaCl. Its molecular weight (or molecular mass) is 58.453 g/mol (23 for the Na + 35.453 for the Cl). Using that 3 mg/kg dosage you propose, means that if you have an animal that weights 1 kg (maybe a very big rat, hehe) you must inject/gavage it with 3 mg of NaCl (Regardless the volume of diluent you want to use to administer those 3 mg).
If you want to know, what is the concentration you need to get those 3 mg of NaCl in your in vitro experiment, you only have to use the molarity formula (M = m/MW * 1/V where m = mass in grams, m = molecular weight of the substance and V = volume of the diluent in litres).
Assuming that you want to prepare 10 mL (V) of such substance for your in vitro experiments and knowing that MW of NaCL = 58.453 g/mol and m = 0.003 g. The resultant concentration (molarity) will be: 0.00000513 molar = 5.13 micro molar
But this is only the mathematical calculations, as Rob said, you can’t assume the same amount of substance for in vivo that for in vitro assays. For example, oral gavaging a rat with 3 mg of substance is not the same as treating an in vitro epithelium of intestinal cells growing over 1.1 cm2 diameter wells. Those 3 mg of substance will probably be very harzadous for the cells (Assuming your substance is harzadous). You must establish the quantity empirically by testing different amount of substance treatments on your cells.
2 Recommendations
Hello! There is no correlation between in vivo and in vitro doses. The only way to find a correct concentration for a specific in vitro study is a time-dependent dose-response curve. For example, some pharmacological inhibitors may act within 30-60 min, they might be reversible or not etc. There are a lot variations that can be eliminated by dose-response curves. Each in vitro model has its own particularity given by cell type, culture conditions, objectives etc.
1 Recommendation
I need to come back researching
Without the help of pharmacokinetic, you may use a dose-dependent curve (1,10,100,1000) to start, and once undertstood the range of efficacy you can refine better. IV treatment require less drug and, initially, by this way of treatment, to have an idea of how much drug to start your dose-dependent curve, you may consider the animal being as a test tube. In IV treatment your drug has to be clearly dissolved. If your drug acts mainly in the liver use only oral administrations
Manipal Academy of Higher Education
In my view, there is no correlation in dose of in-vivo and in-vitro treatments and we can not extrapolate the dose from each other's dose. Both are different. As all knows in-vitro is a preliminary research to get the property of test compounds and of-course some extent pharmacodynamics. In in-vitro we work on a single or isolated cell; whereas in in-vivo with different tissues which interacts with each others physiology always. So, we can not convert either dose.
The wide range of efficacy dose selection can be done after cytotoxicity (in-vitro) and rodent toxicity study (in-vivo) by following some guidelines. By doing PK studies and PD studies in rodents we come to a fixed efficacy dose. Both research has different profile (even though same target). Finding a suitable dose in in-vitro or in-vivo is a systematic and long individual procedure. So, we can not convert either dose.
1 Recommendation
National University of Malaysia
Is there's a way of finding a suitable concentration or conversion of an in-vivo dose of say 250 mg/kg of potassium oxonate or oxonic acid in mouse to be used in in-vivo dose in zebrafish? Can we then establish a correlation between the the zebrafish and mice based on that dose or concentration?
2 Recommendations
Roche
It's quite complicated to convert from in vitro to in vivo or vice versa. Many many modifications and ADME-properties can drastically change the activity of compound that you are testing. Still following methods can be used for an approximation of the drug dosages!
Say you`re working with a drug - DRUG X with clinical dosage of 100 mg/m2.
Method 1:
Clinical dosage of DRUG X is 100 mg/m2.
Assuming that we`re doing viability assay in 96 well plates. The surface area of a single well in 96 well plate is 0.32 cm2, which means that we will need the following equivalent in vitro dose in each well = 100*3.2e-5 = 0.0032 mg.
Now, in order to calculate the concentration of 0.0032 mg of DRUG X for in vitro experiment, we can use the molarity formula (M = m/MW * 1/V where m = mass in grams, MW = molecular weight of the substance and V = volume of the diluent in litres).
We need 0.0032 mg of DRUG X in 100 µL or 0.0001 L (V) for our in vitro experiments (96-well plate) and knowing that MW of DRUG X = 588.72 g/mol and m = 0.0000032 g.
The resultant concentration (molarity) will be: 0.00005435 M or 54.35 µM.
Method 2:
Clinical dosage of DRUG X is 100 mg/m2.
Mice dosage in mg/kg = Human Equivalent Dosage in mg/m2 / Mice Km = 100 / 3 = 33.3 mg/kg
Assuming that average mouse weight is 25 gms, amount of DRUG X administered to each mouse = (33.3/1000)*25 = 0.8325 mg
Now, in order to calculate the concentration of 0.8325 mg of DRUG X in our in vitro experiment, we can use the molarity formula (M = m/MW * 1/V where m = mass in grams, MW = molecular weight of the substance and V = volume of the diluent in litres).
Assuming that we would like to make 25 ml or 0.025 L (V) of DRUG X solution for our in vitro experiments (assumption is 25g mice as 25ml volume) and knowing that MW of DRUG X = 588.72 g/mol and m = 0.0008325 g.
The resultant concentration (molarity) will be: 0.00005656 M or 56.56 µM.
As mentioned earlier, these calculations are just approximations!
3 Recommendations
Sichuan University
Converting an in vivo dose to an in vivo concentration or vice versa is a complex task, primarily due to the dynamic nature of drug distribution, metabolism, and elimination within a living organism. However, there are some pharmacokinetic principles and models that can be applied to estimate this conversion, keeping in mind that these estimates often involve approximations and assumptions.
### Key Concepts and Steps
1. **Volume of Distribution (Vd)**: This is a key parameter in pharmacokinetics. The volume of distribution is a theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration as it is observed in the blood plasma.
- **Formula**: \( Vd = \frac{\text{Amount of drug in the body}}{\text{Plasma drug concentration}} \)
2. **Initial Concentration (C0)**: Immediately after intravenous (IV) administration, the initial concentration can be estimated using the dose and the volume of distribution.
- **Formula**: \( C_0 = \frac{\text{Dose}}{Vd} \)
3. **Dose to Concentration**: For a given dose, you can estimate the initial concentration using the above formula. However, for other routes of administration (like oral), bioavailability and absorption kinetics must also be considered.
4. **Concentration to Dose**: To find the dose from a known concentration, you would typically use the volume of distribution. If you know the desired concentration and the volume of distribution, you can estimate the dose.
- **Formula**: \( \text{Dose} = C \times Vd \)
5. **Accounting for Pharmacokinetics**: Realistically, this conversion is not straightforward due to the complexity of drug kinetics in the body. Factors like metabolism, elimination (half-life), and dynamic distribution in different tissues complicate the conversion.
6. **Model-Based Approaches**: Pharmacokinetic models (like one-compartment or multi-compartment models) can be used to more accurately predict how concentrations change over time following a dose.
### Important Considerations
- **Interindividual Variability**: There's significant variability in how different individuals process medications, so these calculations often provide a general estimate.
- **Drug Properties**: Lipophilicity, protein binding, and other chemical properties of the drug affect distribution and concentration.
- **Route of Administration**: Oral, IV, intramuscular, and other routes have different absorption and bioavailability profiles.
### Conclusion
While it's possible to estimate in vivo concentration from a given dose or vice versa, such estimates are inherently approximate. Detailed pharmacokinetic studies and models are often necessary for more precise conversions, especially for new or less-studied drugs. These calculations should always be approached with caution and within the context of comprehensive pharmacokinetic understanding.
l Take a look at this protocol list; it could assist in understanding and solving the problem.
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