Potential role for P-glycoprotein in the non-proportional 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, 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 = 76 microM for this enzyme, saturation of first-pass metabolism alone was considered unlikely to account for the non-proportional pharmacokinetics. 3. UK-343,664 showed high affinity for P-glycoprotein in vitro, with a Km = 7.3 microM. In transport studies in LLC-PK1 cell monolayers transfected with P-glycoprotein, UK343,664 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.
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Department of  Clinical Sciences, Pfizer Global Research and Development, Sandwich, UK.
Beaumont
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Crespi
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Eve
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MD
Fox
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Hyland
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Jones
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Muirhead
G J
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Smith
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Venn
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Walker
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D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000818:Animals; D001693:Biological Transport, Active; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D018374:LLC-PK1 Cells; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D010879:Piperazines / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D011485:Protein Binding; D011744:Pyrimidinones / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000378:metabolism; D013552:Swine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011744:Pyrimidinones; D011994:Recombinant Proteins; C450961:UK 343,664; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human