Pharmacokinetic interaction between verapamil and metoprolol in the dog. Stereochemical aspects.
The effect of verapamil co-administration on the hepatic first-pass clearance of metoprolol was investigated in dogs. Plasma concentration-time course of metoprolol enantiomers and urinary recovery of oxidative metabolites were determined after a single iv (0.51 mg/kg) and an oral (1.37 mg/kg) dose of deuterium-labeled pseudoracemic metoprolol, with or without concomitant administration of racemic verapamil (3 mg/kg). Verapamil inhibited both the systemic and oral clearance of metoprolol by about 50-70%. The first-pass effect of metoprolol was completely abolished after co-administration of verapamil, reflecting a marked alteration in the degree of hepatic extraction of metoprolol from intermediate to low. The hepatic clearance of metoprolol was slightly (S)-enantioselective (R/S ratio = 0.89 +/- 0.04) in control dogs. Inhibition of hepatic clearance of metoprolol by verapamil was selective towards (S)-metoprolol, such that the enantioselectivity in hepatic clearance toward (S)-metoprolol disappeared following verapamil co-administration (R/S ratio = 1.01 +/- 0.05). Urinary metabolite profiles indicated that O-demethylation and N-dealkylation were the major pathways of oxidative metabolism in the dog. alpha-Hydroxymetoprolol was a minor metabolite in urine. N-Dealkylation showed a strong preference for (S)-metoprolol, whereas O-demethylation and alpha-hydroxylation exhibited a modest selectivity toward (R)-metoprolol; hence, the slight (S)-enantioselectivity in the overall hepatic clearance. Comparison of metoprolol metabolite formation clearances in the absence or presence of verapamil co-administration showed that all three oxidative pathways were inhibited by 60-80%. The greater inhibition of hepatic clearance observed with (S)-metoprolol as compared to (R)-metoprolol was attributed to a significant (S)-enantioselective inhibition in the O-demethylation of metoprolol by verapamil.
Murthy
S S
SS
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Nelson
W L
WL
Shen
D D
DD
Power
J M
JM
Cahill
C M
CM
McLean
A J
AJ
D000284:Administration, Oral; D000478:Alkylation; D000818:Animals; D001682:Biological Availability; D003903:Deuterium; D004285:Dogs; D004347:Drug Interactions; D005260:Female; D006900:Hydroxylation; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008790:Metoprolol / Q000378:metabolism / Q000493:pharmacokinetics*; D010084:Oxidation-Reduction; D013237:Stereoisomerism; D014700:Verapamil / Q000378:metabolism / Q000493:pharmacokinetics*
D003903:Deuterium; D014700:Verapamil; D008790:Metoprolol