A mathematic model has been developed to describe the time course of 2-amino-1,3,4-thiadiazole and its metabolites in the serum and tissues of mice, dogs, and monkeys. A flow-limited physiologic model has been used. The rate of metabolism in mice is described as a linear process; metabolism in dogs and monkeys is kinetically saturable. The urinary excretion in mice, dogs, and monkeys is described as a linear process; however, the kidney clearance in monkeys may decrease at high plasma concentrations. The model predictions are compared with published data. The kidney clearances of 2-amino-1,3,4-thiadiazole and its metabolites exhibit approximately a 0.7-power dependence on body weight when the mouse is compared with the larger species.

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PubMedDate not supplied

Pharmacokinetic considerations on resistance to anticancer drugs.

A model framework is discussed for a quantitative description of intercompartment drug transport in terms of individual processes involved. It permits joint consideration of blood flow, membrane transport, binding, and enzyme synthesis. Illustrations are drawn from the pharmacokinetics and pharmacodynamics of methotrexate. Special cases include flow and membrane limitation, and a simple expression is derived to estimate the time required for intracellular drug to reach the concentration of high-affinity binding sites. Transport parameters between blood and cerebrospinal fluid are inferred from new clinical data. Lumbar injection provided a reservoir effect which maintained plasma concentration for a prolonged time compared with intravenous injections.

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PubMedDate not supplied

A preliminary pharmacokinetic model for several chlorinated biphenyls in the rat.

A mathematical model is presented to describe the kinetics of distribution, metabolism, and excretion of 4-chloro-, 4,4'-dichloro-, 2,2',4,5,5'-pentachloro-, and 2,2',4,4',5,5'-hexachlorobiphenyl in rats given an intravenols dose of 0.6 mg/kg. A modified flow-limited model simulates the penta- and hexachlorobiphenyl data for periods up to 96 hr but underestimates the mono- and dichlorobiphenyl data beyond 48 hr. The rate constant for metabolism by the liver decreases as degree of chlorination increases such that the rate constant is 200 times smaller for the hexachlorobiphenyl than for the monochlorobiphenyl. The value of the biliary clearance of metabolites is nearly the same for each chlorinated biphenyl, whereas the value of the urinary clearance decreases with increasing degree of chlorination, being 10 times smaller for hexachlorobiphenyl than for monochlorophenyl. The distribution coefficients between most tissues and blood are larger for each parent compound than for its metabolites. Hexachlorobiphenyl has the largest distribution coefficient of all the chlorinated biphenyls in each tissue, whereas the mono-, di-, and pentachlorobiphenyls show no consistent variation. For each compound the distribution coefficient is greater in the fat than in any other tissue. Changes in the fat volume of the growing rats were incorporated into the model in order to simulate the hexachlorobiphenyl concentrations in blood and fat for 42 days.

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PubMedDate not supplied

Estimation of Lymphatic Absorption and Intraperitoneal Volume During Hypertonic Peritoneal Dialysis.

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Absorption↗

PubMedDate not supplied

Comparison of the pharmacokinetics of several polychlorinated biphenyls in mouse, rat, dog, and monkey by means of a physiological pharmacokinetic model.

Physiologic pharmacokinetic analysis of 4,4'-dichlorobiphenyl, 2,2',3,3',6,6'-hexachlorobiphenyl, and 2,2',4,4',5,5'-hexachlorobiphenyl is presented for the dog and monkey, and the results are compared with previous similar analyses for the rat and mouse. The normalized clearances (ml/min/kg body weight) vary considerably between the dog and the monkey; the rat and the mouse show less species variation. The equilibrium tissue-to-blood distribution ratios for parent and metabolite are generally similar for all four species. The fat compartment has the highest parent distribution ratio for all four species, and the metabolite distribution ratios are much smaller than the parent distribution ratios. Metabolism appears to be a prerequisite to urinary and biliary excretion for all three compounds in each species. Elimination from the body occurs predominantly by the fecal route. The 2,2',4,4',5,5'-hexachlorobiphenyl is more slowly metabolized than the 2,2',3,3',6,6'-isomer in all species, which supports the contention that two adjacent, unsubstituted carbon atoms on the biphenyl ring promote more rapid metabolism.

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