RT Journal Article
SR Electronic
T1 In Vitro Biotransformation of Sildenafil (Viagra) in the Male Rat: The Role of CYP2C11
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 655
OP 657
DO 10.1124/dmd.30.6.655
VO 30
IS 6
A1 Jill S. Warrington
A1 Lisa L. von Moltke
A1 Richard I. Shader
A1 David J. Greenblatt
YR 2002
UL http://dmd.aspetjournals.org/content/30/6/655.abstract
AB To assess the suitability of the male rat model for human studies on sildenafil metabolism, we examined the biotransformation of sildenafil in male rat liver microsomes and identified the role of specific cytochrome P450s (P450) using inhibitory antibodies and cDNA-expressed P450s. Rates of formation of the major circulating metabolite of sildenafil, UK-103,320, were 11-fold greater in the male rat than in human liver microsomes at 36 μM sildenafil, whereas substrate concentration corresponding to 50%Vmax (Km values) were 2.9-fold lower in the male rat. Although sildenafil is largely metabolized by CYP3A isoforms in humans, coincubation of rat liver microsomes with immunoinhibitory antibodies (CYP1A1/2, 2B1/2, 2C11, 2E1, and 3A1/2) revealed that metabolite formation was inhibited only by an antirat CYP2C11 antibody. Incubation of sildenafil with a cDNA-expressed CYP2C11 produced 10-fold higher levels of UK-103,320 than other P450s (CYP1A1, 1A2, 2B1, 2C6, 2C12, 2C13, 2E1, 3A1, and 3A2). Thus CYP2C11 contributes in a major way to the metabolism of sildenafil in the male rat. P450 isoforms mediating sildenafil biotransformation differ substantially between humans and the male rat, thereby limiting the applicability of this species as a model for sildenafil metabolism and drug interactions in humans. The American Society for Pharmacology and Experimental Therapeutics