title: Effects of oxazepam and acetaminophen on cicletanine metabolism in rat hepatocytes and liver microsomes.
abstract: Cicletanine, a racemic furopyridine derivative synthesized as racemate, is used as an antihypertensive agent. Its two enantiomers are involved in the pharmacological effects of the drug. Cicletanine is metabolized by conjugation enzyme systems (phase II) into sulfoconjugated or glucuroconjugated enantiomers. As oxazepam and acetaminophen are widely prescribed, especially to elderly patients, these two drugs may be co-administered with cicletanine. The metabolic profile and the kinetics of biotransformation were studied by using rat hepatocytes and liver microsomes. Cicletanine was extensively metabolized by rat hepatocytes. More than 80% of the drug was biotransformed after a 3 h incubation. The formation of glucuroconjugated metabolites was characterized by the following kinetic parameters, i.e. Vmax = 2.05 +/- 0.21 nmol/min/mg protein and Km = 287 +/- 6.7 microM for (-)-cicletanine, and Vmax = 1.44 +/- 0.12 nmol/min/mg protein and K(m) = 171 +/- 4.1 microM for (+)-cicletanine. Oxazepam inhibited the glucuronidation of cicletanine in both rat hepatocytes and liver microsomes with a competitive-type inhibition, i.e. K(i) = 129 +/- 7.5 and 152 +/- 19.7 microM for (-)-cicletanine and (+)-cicletanine, respectively. The co-incubation of acetaminophen with cicletanine showed that only sulfoconjugation was inhibited in rat hepatocytes. Glucuronidation was not modified by acetaminophen. As natriuric activity is due to sulfoconjugated (+)-cicletanine, acetaminophen could potentially modulate in vivo the pharmacological effect of cicletanine. The data of the in vitro study reported here suggested an interaction between cicletanine and oxazepam or cicletanine and acetaminophen. However, the clinical impact of such a drug interaction needs further evaluation.
authors.affiliation: Laboratoire de Pharmacologie, EA-948 and 13S, Faculté de Médecine, Brest, France.
authors.forename: C
authors.initials: C
authors.lastname: Menard
authors.forename: D
authors.initials: D
authors.lastname: Lamiable
authors.forename: R
authors.initials: R
authors.lastname: Vistelle
authors.forename: M T
authors.initials: MT
authors.lastname: Droy-Lefait
authors.forename: D
authors.initials: D
authors.lastname: Ratanasavanh
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010076:Oxazepam / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
chemical_list: D011725:Pyridines; D000082:Acetaminophen; D010076:Oxazepam; C038068:cicletanine