Model-independent definition of the initial volume of distribution of drugs in the body.

Model-independent definition of the initial volume of distribution of drugs in the body as a limit of the ratio of the drug content in the body to its blood concentration with time from the start of drug administration tending towards zero is given. This definition makes it possible to calculate the initial volume of distribution as the ratio of the initial rate of drug administration to the value of the first derivative of the blood-concentration-time curve at the start of administration. The definition proposed enables one to overcome difficulties of the conventional definition of the initial volume of distribution (as the ratio of the dose administered to the initial blood concentration of a drug). Two methods for estimating the first derivative of the concentration-time curve are compared. The first one requires a single measurement of the drug concentration in blood at the time point as close as possible to the start of administration. The value of the derivative is calculated as the ratio of the drug concentration to the time of blood sampling. The second method requires at least two measurements of drug concentration during administration at various time points and consists in approximating the time dependence of the derivative by an exponential function. The value of the derivative at the start of administration can be found by extrapolation of the function to zero. The application of the methods proposed is illustrated by examples of calculating the initial volume of distribution from the data simulated by a computer on the basis of a two-compartment model.(ABSTRACT TRUNCATED AT 250 WORDS)