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 30-800 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.
MeSH terms
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3',5'-Cyclic-GMP Phosphodiesterases / antagonists & inhibitors*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
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Administration, Oral
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Adolescent
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Adult
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Animals
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Biological Transport, Active
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Cyclic Nucleotide Phosphodiesterases, Type 5
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme System / metabolism
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Humans
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In Vitro Techniques
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LLC-PK1 Cells
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Male
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Microsomes, Liver / metabolism
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Middle Aged
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Mixed Function Oxygenases / metabolism
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Phosphodiesterase Inhibitors / administration & dosage
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Phosphodiesterase Inhibitors / analysis
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Phosphodiesterase Inhibitors / pharmacokinetics*
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Piperazines / administration & dosage
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Piperazines / analysis
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Piperazines / pharmacokinetics*
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Protein Binding
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Pyrimidinones / administration & dosage
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Pyrimidinones / analysis
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Pyrimidinones / pharmacokinetics*
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Recombinant Proteins / metabolism
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Swine
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Phosphodiesterase Inhibitors
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Piperazines
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Pyrimidinones
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Recombinant Proteins
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UK 343,664
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Cytochrome P-450 Enzyme System
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Mixed Function Oxygenases
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CYP3A protein, human
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human
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3',5'-Cyclic-GMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 5
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PDE5A protein, human