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

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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, C_max and AUC_t 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 D_7.4 = 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 K_m

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

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

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