ISSN:
1573-904X
Keywords:
drug interaction
;
mechanism-based inhibition
;
triazolam
;
erythromycin
;
physiologically-based pharmacokinetics
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract Purpose. To quantitatively predict the in vivo interaction betweentriazolam and erythromycin, which involves mechanism-basedinhibition 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 thepresence of NADPH and then triazolam was added. α- and 4-hydroxy(OH) triazolam were quantified after a 3 min incubation and the kineticparameters for enzyme inactivation (kinact and K′ app) were obtained.Drug-drug interaction in vivo was predicted based on aphysiologically-based pharmacokinetic (PBPK) model, using triazolam anderythromycin pharmacokinetic parameters obtained from the literature and kineticparameters for the enzyme inactivation obtained in the in vitro studies. Results. Whichever enzyme was used, triazolam metabolism was notinhibited without preincubation, even if the erythromycin concentrationwas increased. The degree of inhibition depended on preincubationtime and erythromycin concentration. The values obtained for kinactand K′ app were 0.062 min−1 and 15.9 μM (α-OH, HLM), 0.055 min−1and 17.4 μM (4-OH, HLM), 0.173 min−1 and 19.1 μM (α-OH, REC),and 0.097 min−1 and 18.9 μM (4-OH, REC). Based on the kineticparameters obtained using HLM and REC, the AUCpo of triazolamwas predicted to increase 2.0- and 2.6-fold, respectively, followingoral administration of erythromycin (333 mg t.i.d. for 3 days), whichagreed well with the reported data. Conclusions. In vivo interaction between triazolam and erythromycinwas successfully predicted from in vitro data based on a PBPK modelinvolving a mechanism-based inhibition of CYP3A4.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1007572803027
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