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Xenobiotica
the fate of foreign compounds in biological systems
Volume 31, 2001 - Issue 8-9
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Research Article

Potential role for P-glycoprotein in the nonproportional pharmacokinetics of UK-343,664 in man

S. Abel Department of Drug Metabolism and Clinical Sciences, Pfizer Global Research and Development, Sandwich CT13 9NJ, UK
,
K. C. Beaumont Department of Drug Metabolism and Clinical Sciences, Pfizer Global Research and Development, Sandwich CT13 9NJ, UK
,
C. L. Crespi Department of Drug Metabolism and Clinical Sciences, Pfizer Global Research and Development, Sandwich CT13 9NJ, UK
,
M. D. Eva Department of Drug Metabolism and Clinical Sciences, Pfizer Global Research and Development, Sandwich CT13 9NJ, UK
,
L. Fox Department of Drug Metabolism and Clinical Sciences, Pfizer Global Research and Development, Sandwich CT13 9NJ, UK
,
R. Hyland Department of Drug Metabolism and Clinical Sciences, Pfizer Global Research and Development, Sandwich CT13 9NJ, UK
,
B. C. Jones Department of Drug Metabolism and Clinical Sciences, Pfizer Global Research and Development, Sandwich CT13 9NJ, UK
,
G. J. Muirhead Department of Drug Metabolism and Clinical Sciences, Pfizer Global Research and Development, Sandwich CT13 9NJ, UK
,
D. A. Smith Department of Drug Metabolism and Clinical Sciences, Pfizer Global Research and Development, Sandwich CT13 9NJ, UK
,
R. F. Venn Department of Drug Metabolism and Clinical Sciences, Pfizer Global Research and Development, Sandwich CT13 9NJ, UK
&
D. K. Walker Department of Drug Metabolism and Clinical Sciences, Pfizer Global Research and Development, Sandwich CT13 9NJ, UK
 show all
Pages 665-676 | Published online: 22 Sep 2008
 
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Abstract

1. UK-343,664 is a potent and specific PDE5 inhibitor. Following single oral doses to human volunteers, it exhibited non-proportional pharmacokinetics over the dose range 30-800mg. Over this 27-fold dose range, Cmax and AUCt increased 247- and 287-fold respectively. The half-life (4-6 h) was similar at all doses. No systemic exposure was quantifiable at doses <10 mg. 2. UK-343,664 is a lipophilic molecule (log D7.4 = 3.1) and as such is expected to be cleared mainly by metabolism. Based on studies with expressed human P450 enzymes it was concluded that the metabolism of UK-343,664 was predominantly mediated by CYP3A4. With a moderate Km

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