Effect of CYP3A inhibition on vesnarinone metabolism in humans

Clin Pharmacol Ther. 1998 May;63(5):506-11. doi: 10.1016/S0009-9236(98)90101-1.


Objective: To identify the cytochrome P450 (CYP) enzymes involved in the conversion of vesnarinone to it main primary metabolite OPC-18692 and to investigate the effect of CYP3A inhibition on the pharmacokinetics of vesnarinone in vivo.

Methods: Formation of the primary vesnarinone metabolite OPC-18692 was measured in microsomes from AHH-1 TK +/- cells heterologously expressing CYP1A1, CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, or CYP3A4. The pharmacokinetics of vesnarinone and OPC-18692 were defined for 12 health white men after oral administration of 60 mg vesnarinone before and after CYP3A inhibition, which was produced by pretreatment with erythromycin. CYP3A inhibition was verified with erythromycin breath test.

Results: In vitro, expressed CYP2E1 and CYP3A4 produced significant amounts of OPC-18692 with the higher formation rate observed by CYP3A4 (12.3 pmol/pmol VYP3A4 per 2 hours versus 1 pmol/pmol CYP2E1 per 2 hours). In vivo, the area under the concentration-time curve extrapolated to infinity (AUC[infinity]) of vesnarinone after pretreatment with erythromycin increased from 133 +/- 26 micrograms.hr/ml to 202 +/- 47 micrograms.hr/ml (p < 0.001), and the half-life increased from 36.5 +/- 9.6 hours to 46.2 +/- 9.2 hours (p < 0.01). Clearance decreased from 372 +/- 68 ml/min to 256 +/- 49 ml/min (p < 0.001). These changes in the disposition of vesnarinone were accompanied by a decrease in plasma concentration of the metabolite OPC-18692 so that the AUC(0-48) was reduced from 1311 +/- 513 micrograms.hr/ml to 850 +/- 148 micrograms.hr/ml (p < 0.001). The total amount of vesnarinone excreted in the urine up to 168 hours after administration increased after erythromycin pretreatment (p < 0.001). Although renal clearance did not change, OPC-18692 was not detectable in the urine. The erythromycin breath test showed significant inhibition after pretreatment with erythromycin (p < 0.001).

Conclusions: CYP2E1 and CYP3A4 are involved in the phase I metabolism of vesnarinone. Inhibition of CYP3A activity in vivo increases the plasma concentration of vesnarinone and delays its elimination in humans so that monitoring of its plasma levels may be helpful in preventing concentration-related toxicity when CYP3A activity is impaired. Whether CYP3A induction and altered CYP2E1 activity may also change the in vivo disposition of vesnarinone remains to be determined.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Anti-Bacterial Agents / pharmacology*
  • Antiviral Agents / metabolism*
  • Antiviral Agents / pharmacokinetics
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / physiology
  • Drug Interactions
  • Erythromycin / pharmacology*
  • Humans
  • Male
  • Metabolic Clearance Rate
  • Oxidoreductases, N-Demethylating / antagonists & inhibitors*
  • Oxidoreductases, N-Demethylating / physiology
  • Pyrazines
  • Quinolines / metabolism*
  • Quinolines / pharmacokinetics


  • Anti-Bacterial Agents
  • Antiviral Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Pyrazines
  • Quinolines
  • vesnarinone
  • Erythromycin
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating