Pharmacokinetic Model for Chlordiazepoxide·HCl in the Dog

Abstract

A six-compartment open-system model is presented to elucidate the physiological disposition of chlordiazepoxide and its two pharmacologically active biotransformation products, Ro 5-0883/1 and Ro 5-2092, in the dog following the intravenous administration of 10 mg./kg. chlordiazepoxide · HCl. The pharmaco-kinetic parameters used in the model were obtained by administering each of the three compounds separately. Excellent agreement was obtained between the plasma levels of intact drug, Ro 5-0883/1, and Ro 5-2092 found after administration of chlordiazepoxide · HCl and the calculated levels of each generated from the model. The main features of chlordiazepoxide disposition were: (a) its complete biotransformation to Ro 5-0883/1; (b) elimination of Ro 5-0883/1 almost entirely by biotransformation with up to 50% proceeding to Ro 5-2092 by oxidative deamination; and (c) elimination of Ro 5-2092 by urinary excretion and further biotransformation.