PURPOSE: To quantitatively predict the in vivo interaction between triazolam and erythromycin, which involves mechanism-based inhibition of CYP3A4, from in vitro studies using human liver microsomes (HLM) and recombinant human CYP3A4 (REC). METHODS: HLM or REC was preincubated with erythromycin in the presence of NADPH and then triazolam was added. alpha- and 4-hydroxy (OH) triazolam were quantified after a 3 min incubation and the kinetic parameters for enzyme inactivation (k(inact) and K('app)) were obtained. Drug-drug interaction in vivo was predicted based on a physiologically-based pharmacokinetic (PBPK) model, using triazolam and erythromycin pharmacokinetic parameters obtained from the literature and kinetic parameters for the enzyme inactivation obtained in the in vitro studies. RESULTS: Whichever enzyme was used, triazolam metabolism was not inhibited without preincubation, even if the erythromycin concentration was increased. The degree of inhibition depended on preincubation time and erythromycin concentration. The values obtained for k(inact) and K('app) were 0.062 min(-1) and 15.9 microM (alpha-OH, HLM), 0.055 min(-1) and 17.4 microM (4-OH, HLM), 0.173 min(-1) and 19.1 microM (alpha-OH, REC), and 0.097 min(-1) and 18.9 microM (4-OH, REC). Based on the kinetic parameters obtained using HLM and REC, the AUCpo of triazolam was predicted to increase 2.0- and 2.6-fold, respectively, following oral administration of erythromycin (333 mg t.i.d. for 3 days), which agreed well with the reported data. CONCLUSIONS: In vivo interaction between triazolam and erythromycin was successfully predicted from in vitro data based on a PBPK model involving a mechanism-based inhibition of CYP3A4.
PURPOSE: To quantitatively predict the in vivo interaction between triazolam and erythromycin, which involves mechanism-based inhibition of CYP3A4, from in vitro studies using human liver microsomes (HLM) and recombinant humanCYP3A4 (REC). METHODS: HLM or REC was preincubated with erythromycin in the presence of NADPH and then triazolam was added. alpha- and 4-hydroxy (OH) triazolam were quantified after a 3 min incubation and the kinetic parameters for enzyme inactivation (k(inact) and K('app)) were obtained. Drug-drug interaction in vivo was predicted based on a physiologically-based pharmacokinetic (PBPK) model, using triazolam and erythromycin pharmacokinetic parameters obtained from the literature and kinetic parameters for the enzyme inactivation obtained in the in vitro studies. RESULTS: Whichever enzyme was used, triazolam metabolism was not inhibited without preincubation, even if the erythromycin concentration was increased. The degree of inhibition depended on preincubation time and erythromycin concentration. The values obtained for k(inact) and K('app) were 0.062 min(-1) and 15.9 microM (alpha-OH, HLM), 0.055 min(-1) and 17.4 microM (4-OH, HLM), 0.173 min(-1) and 19.1 microM (alpha-OH, REC), and 0.097 min(-1) and 18.9 microM (4-OH, REC). Based on the kinetic parameters obtained using HLM and REC, the AUCpo of triazolam was predicted to increase 2.0- and 2.6-fold, respectively, following oral administration of erythromycin (333 mg t.i.d. for 3 days), which agreed well with the reported data. CONCLUSIONS: In vivo interaction between triazolam and erythromycin was successfully predicted from in vitro data based on a PBPK model involving a mechanism-based inhibition of CYP3A4.
Authors: T Iwatsubo; N Hirota; T Ooie; H Suzuki; N Shimada; K Chiba; T Ishizaki; C E Green; C A Tyson; Y Sugiyama Journal: Pharmacol Ther Date: 1997 Impact factor: 12.310
Authors: Shufeng Zhou; Sui Yung Chan; Boon Cher Goh; Eli Chan; Wei Duan; Min Huang; Howard L McLeod Journal: Clin Pharmacokinet Date: 2005 Impact factor: 5.577