Abstract

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 metabolism. Incubation of 10 μM [¹⁴C]delavirdine with either an S9 fraction 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 formation of three significant metabolites. The major metabolite was desalkyl delavirdine; however, the identity of MET-7 and MET-7a (defined by high pressure liquid chromatography elution) could not be unambiguously established, but they seem to be related pyridine hydroxy metabolites, most likely derived from 6′-hydroxylation of the pyridine ring. The apparent K_M for delavirdine desalkylation activity ranged from 4.4 to 12.6 μM for human, rat, monkey, and dog microsomes, whereas V_maxranged from 0.07 to 0.60 nmol/min/mg protein, resulting in a wide range of intrinsic clearance (6–135 μL/min/mg protein). Delavirdine desalkylation by microsomes pooled from several human livers was characterized by a K_M of 6.8 ± 0.8 μM 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 6β-hydroxylation, an indicator of CYP3A activity. Among ten human microsomal samples selected for uniform distribution of CYP3A activity, formation of MET-7 was strongly correlated with CYP3A activity (r = 0.95) and with delavirdine desalkylation (r = 0.98). Delavirdine desalkylation was catalyzed by cDNA-expressed CYP2D6 (K_M 10.9 ± 0.8 μM) and CYP3A4 (K_M 5.4 ± 1.4 μM); however, only CYP3A4 catalyzed formation of MET-7 and MET-7a. Quinidine inhibited human liver microsomal delavirdine desalkylation by about 20%, indicating a minor role of CYP2D6. These findings suggest the potential for clinical interaction with coadministered drugs that are metabolized by or influence the activity of CYP3A or CYP2D6.