title: 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.
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 microM [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 KM for delavirdine desalkylation activity ranged from 4.4 to 12.6 microM for human, rat, monkey, and dog microsomes, whereas Vmax ranged from 0.07 to 0.60 nmol/min/mg protein, resulting in a wide range of intrinsic clearance (6-135 microL/min/mg protein). Delavirdine desalkylation by microsomes pooled from several human livers was characterized by a KM of 6.8 +/- 0.8 microM and Vmax 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 6beta-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 (KM 10.9 +/- 0.8 microM) and CYP3A4 (KM 5.4 +/- 1.4 microM); 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.
authors.affiliation: Drug Metabolism Research, Pharmacia and Upjohn, Kalamazoo, MI 49007, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Voorman
authors.forename: S M
authors.initials: SM
authors.lastname: Maio
authors.forename: M J
authors.initials: MJ
authors.lastname: Hauer
authors.forename: P E
authors.initials: PE
authors.lastname: Sanders
authors.forename: N A
authors.initials: NA
authors.lastname: Payne
authors.forename: M J
authors.initials: MJ
authors.lastname: Ackland
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000502:physiology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D020008:Delavirdine / Q000378:metabolism*; D004285:Dogs; D005260:Female; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000502:physiology*; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism*
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D020008:Delavirdine; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human