NDLI: Prediction of In Vivo Interaction Between Triazolam and Erythromycin Based on In Vitro Studies Using Human Liver Microsomes and Recombinant Human CYP3A4

Content Provider	Springer Nature Link
Author	Kanamitsu, Shin ichi Ito, Kiyomi Green, Carol E. Tyson, Charles A. Shimada, riaki Sugiyama, Yuichi
Copyright Year	2000
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 (k$_{inact}$ 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 k$_{inact}$and K$^{′}$ $_{app}$ were 0.062 min$^{−1}$ and 15.9 μM (α-OH, HLM), 0.055 min$^{−1}$and 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.
Starting Page	419
Ending Page	426
Page Count	8
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	17
Issue Number	4
e-ISSN	1573904X
Language	English
Publisher	Kluwer Academic Publishers-Plenum Publishers
Publisher Date	2000-01-01
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pharmacology/Toxicology Pharmacy Biochemistry Medical Law Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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