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

Xenobiotica. 2001 Aug-Sep;31(8-9):665-76. doi: 10.1080/00498250110052779.

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.

Publication types

  • Validation Study

MeSH terms

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

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Phosphodiesterase Inhibitors
  • Piperazines
  • Pyrimidinones
  • Recombinant Proteins
  • UK 343,664
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • PDE5A protein, human