title: In vitro assessment of stereoselective hepatic metabolism of disopyramide in humans: comparison with in vivo data.
abstract: Metabolism of disopyramide (DP) enantiomers has been investigated in primary cultures of adult human hepatocytes. Results were compared with in vivo data obtained from a previous pharmacokinetic study (Le Corre et al. Drug Metab. Dispos. 16:858-864 1988). Metabolism of DP enantiomers as a function of incubation time showed constant velocity over time. The intracellular/extracellular distribution of both DP and mono-N-desisopropyldisopyramide did not appear to be stereoselective. Metabolism of DP enantiomers as a function of substrate concentration followed a first order kinetics. The average fractions of (-)-(R)-DP and (+)-(S)-DP metabolized in vitro (4.7 +/- 2.7 and 7.1 +/- 4.2%, respectively, n = 4) were about 5-fold lower than the fractions metabolized in vivo (26.0 +/- 6.0 and 40.2 +/- 8.8%, respectively, n = 6). The stereoselective index [(+)-(S)/(-)-(R)] of the N-dealkylation pathway obtained in vitro (1.51 +/- 0.11, n = 4) was very close to the one obtained in vivo (1.55 +/- 0.10, n = 6). These results highlight the interest of hepatocyte cultures in the evaluation of drug metabolism and especially in the assessment of stereoselectivity.
authors.affiliation: Laboratoire de Pharmacie Galénique et Biopharmacie, Université de Rennes, France.
authors.forename: P
authors.initials: P
authors.lastname: Le Corre
authors.forename: D
authors.initials: D
authors.lastname: Ratanasavanh
authors.forename: F
authors.initials: F
authors.lastname: Chevanne
authors.forename: D
authors.initials: D
authors.lastname: Gibassier
authors.forename: P
authors.initials: P
authors.lastname: Sado
authors.forename: R
authors.initials: R
authors.lastname: Le Verge
authors.forename: A
authors.initials: A
authors.lastname: Guillouzo
mesh_terms: D000328:Adult; D001711:Biotransformation; D004206:Disopyramide / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D013237:Stereoisomerism
chemical_list: C030438:4-(isopropylamino)-2-(2-pyridyl)-2-phenylbutyramide; D004206:Disopyramide