Safety Evaluation and Drug Development based on Biological Fate of Drugs —Efforts Made to Overcome Drug Interaction in Drug Development—

Abstract

1. Assay methods to detect drug interaction in toxicological samples were established by determining cytochrome P450 content and its activity in liver samples. The O-dealkylation reaction of 7-alkoxycoumarin was indicated to reflect changes in the molecular forms of P450s, and the enzyme induction or inhibition in the toxicological samples was easily detected by using the established methods. 2. During toxicological studies of 450191-S or the sleep inducer rilmazafone, a phenobarbital type-induction of hepatic drug metabolizing enzymes was observed in animals, and the doses required for the induction differed markedly between rats and dogs. Enzyme induction was caused by some specific metabolites of 450191-S, and the plasma concentrations of these metabolites were comparable when the enzyme induction was developed in both animals. 3. A nonsteroidal antiinflammatory compound 480156-S showed a slight or no effect on microsomal drug metabolizing activity in rats. On the other hand, repeated administration of this compound to humans resulted in a marked decrease in the oxidative metabolism of 480156-S, followed by a marked increase in the plasma concentrations of the compound. When volunteers were given 480156-S followed by several drugs, such as tolubutamide, the plasma clearance was delayed remarkably, indicating a severe drug interaction. 4. Cytochrome P450 belonging to the CYP2C family was indicated to participate in the oxidative metabolism of 480156-S in both rat and human liver microsomes. The preincubation of microsomes with 480156-S caused a concentration-dependent inhibition of CYP2C-dependent tolubutamide hydroxylation reaction in both rats and humans. There was a marked species difference in the susceptibility to the inhibitory effect of 480156-S, and the concentration required to inhibit rat CYP2C was almost 10 times higher than that required in humans. 5. The cephem antibiotics having N-methyltetrazolethiol (NMTT) at the 3'-position substituent were demonstrated to inhibit mitochondrial low K(m) aldehyde dehydrogenase (ALDH), and produced disulfiram-like (Antabuse) reaction during alcohol metabolism. Pharmacokinetic studies indicated that NMTT released from the antibiotics in bile duct or intestine cause the inhibitory action followed by the development of disulfiram-like reaction. 6. Attempts had been made to develop new cephem antibiotics lacking the disulfiram-like reaction by changing the chemical structure of 3'-position substituents, and a hydroxyethyltetrazolethiol was found not to inhibit the enzyme. Based on this result, together with the antibacterial activity, we have developed a new oxacephem antibiotic flomoxef (6315-S). Flomoxef showed no disulfiram-like reaction both in rats and human.