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

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 30-800 mg. 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=76 <mu>m for this enzyme, saturation of first-pass metabolism alone was considered unlikely to account for the non-proportional pharmacokinetics. . UK- 343,664 showed high affinity for P-glycoprotein in vitro, with a K-m=7.3 mum. In transport studies in LLC-PK1 cell monolayers transfected with P-glycoprotein, UK-343,664 showed marked polarized transport which was concentration dependent. 4. The high affinity of UK- 343,664 for P-glycoprotein is considered to be the primary source of the non-proportional pharmacokinetic profile observed in man.