Pharmacokinetic interaction between oral lovastatin and verapamil in healthy subjects: role of P-glycoprotein inhibition by lovastatin

Eur J Clin Pharmacol. 2010 Mar;66(3):285-90. doi: 10.1007/s00228-009-0757-x. Epub 2009 Dec 12.

Abstract

Background: Lovastatin is an inhibitor of P-glycoprotein (P-gp) and is metabolized by the cytochrome P450 (CYP) 3A4 isoenzyme. Verapamil is a substrate of both P-gp and CYP3A4. It is therefore likely that lovastatin can alter the absorption and metabolism of verapamil.

Methods: The pharmacokinetic parameters of verapamil and one of its metabolites, norverapamil, were compared in 14 healthy male Korean volunteers (age range 22-28 years) who had been administered verapamil (60 mg) orally in the presence or absence of oral lovastatin (20 mg). The design of the experiment was a standard 2 x 2 crossover model in random order.

Results: The pharmacokinetic parameters of verapamil were significantly altered by the co-administration of lovastatin compared to the control. The area under the plasma concentration-time curve (AUC (0-infinity)) and the peak plasma concentration of verapamil were significantly increased by 62.8 and 32.1%, respectively. Consequently, the relative bioavailability of verapamil was also significantly increased (by 76.5%). The (AUC (0-infinity)) of norverapamil and the terminal half-life of verapamil did not significantly changed with lovastatin coadministration. The metabolite-parent ratio was significantly reduced (29.2%) in the presence of lovastatin.

Conclusion: Lovastatin increased the absorption of verapamil by inhibiting P-gp and inhibited the first-pass metabolism of verapamil by inhibiting CYP3A4 in the intestine and/or liver in humans.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Administration, Oral
  • Adult
  • Area Under Curve
  • Asian Continental Ancestry Group
  • Biological Availability
  • Blood Pressure / drug effects
  • Calcium Channel Blockers / administration & dosage
  • Calcium Channel Blockers / blood
  • Calcium Channel Blockers / pharmacokinetics*
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 CYP3A Inhibitors*
  • Drug Interactions
  • Enzyme Inhibitors / administration & dosage*
  • Half-Life
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage*
  • Intestinal Absorption / drug effects
  • Korea
  • Lovastatin / administration & dosage*
  • Male
  • Verapamil / administration & dosage
  • Verapamil / analogs & derivatives
  • Verapamil / blood
  • Verapamil / pharmacokinetics*
  • Young Adult

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Calcium Channel Blockers
  • Cytochrome P-450 CYP3A Inhibitors
  • Enzyme Inhibitors
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • norverapamil
  • Lovastatin
  • Verapamil
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human