Selective induction of propranolol metabolism by smoking: additional effects on renal clearance of metabolites.
The objective of this study was to examine the effect of cigarette smoking on the activities of the three primary pathways governing propranolol metabolism in human subjects, i.e., glucuronidation, side-chain oxidation and ring oxidation. A single 80-mg dose of propranolol p.o. together with 40 muCi of 4-[3H]propranolol was given to six smoking and seven nonsmoking, young, white, male subjects and the oral clearance of propranolol and the partial clearances through these pathways were determined. The oral clearance of propranolol was increased by 77% (P less than .02) in smokers compared with nonsmokers. This apparent induction of propranolol metabolism was due to a 122% increase in side-chain oxidation (P less than .001) and a 55% increase in glucuronidation (P less than .01). There was no significant effect of smoking on aromatic ring oxidation. Smokers had a 30% greater renal clearance of total metabolites (P less than .05), due mainly to a 53% greater renal clearance of the acidic propranolol metabolite naphthoxylactic acid (P less than .001). These data show a selective effect of smoking on propranolol metabolism and suggest that side-chain oxidation and glucuronidation are mediated by isoenzymes inducible by aromatic hydrocarbons. The selective effect of smoking on the renal clearance of the major propranolol metabolite naphthoxylactic acid may be due to induction of a renal transport protein.
D000328:Adult; D003404:Creatinine / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007773:Lactates / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D011433:Propranolol / Q000031:analogs & derivatives / Q000378:metabolism*; D012907:Smoking
D007773:Lactates; C002685:naphthoxylactic acid; C022056:propranolol glucuronide; C043288:4-hydroxypropranolol glucuronide; D011433:Propranolol; D003404:Creatinine