METABOLISM OF DELAVIRDINE, A HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REVERSE-TRANSCRIPTASE INHIBITOR, BY MICROSOMAL CYTOCHROME-P450 IN HUMANS, RATS, AND OTHER SPECIES - PROBABLE INVOLVEMENT OF CYP2D6 AND CYP3A

The metabolism of delavirdine was examined using liver microsomes from several species with the aim of comparing metabolite formation among species and characterizing the enzymes responsible for delavirdine met abolism, Incubation of 10 mu M [C-14]delavirdine with either an S9 fra ction from human jejunum or liver microsomes from rat, human, dog, or monkey followed by high pressure liquid chromatography analysis showed qualitatively similar metabolite profiles among species with the form ation of three significant metabolites. The major metabolite was desal kyl delavirdine; however, the identity of MET-7 and MET-7a (defined by high pressure liquid chromatography elution) could not be unambiguous ly established, but they seem to be related pyridine hydroxy metabolit es, most likely derived from 6'-hydroxylation of the pyridine ring, Th e apparent K-M for delavirdine desalkylation activity ranged from 4.4 to 12.6 mu M for human, rat, monkey, and dog microsomes, whereas V-max ranged from 0.07 to 0.60 nmol/min/mg protein, resulting in a wide ran ge of intrinsic clearance (6-135 mu L/min/mg protein), Delavirdine des alkylation by microsomes pooled from several human livers was characte rized by a K-M of 6.8 +/- 0.8 mu M and V-max of 0.44 +/- 0.01 nmol/min /mg, Delavirdine desalkylation among 23 human liver microsomal samples showed a meaningful correlation (r = 0.96) only with testosterone 6 b eta-hydroxylation, an indicator of CYP3A activity, Among ten human mic rosomal samples selected for uniform distribution of CYP3A activity, f ormation of MET-7 was strongly correlated with CYP3A activity (r = 0.9 5) and with delavirdine desalkylation (r = 0.98). Delavirdine desalkyl ation was catalyzed by cDNA-expressed CYP2D6 (K-M 10.9 +/- 0.8 mu M) a nd CYP3A4 (K-M 5.4 +/- 1.4 mu M); however, only CYP3A4 catalyzed forma tion of MET-7 and MET-7a, Quinidine inhibited human liver microsomal d elavirdine desalkylation by about 20%, indicating a minor role of CYP2 D6, These findings suggest the potential for clinical interaction with coadministered drugs that are metabolized by or influence the activit y of CYP3A or CYP2D6.