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

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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.

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Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Shin-ichi Kanamitsu

  2. School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shiro-kane, Minato-ku, Tokyo, 108-8641, Japan

    Kiyomi Ito

  3. Toxicology Laboratory, SRI International, 333 Ravenswood Avenue, Menlo Park, California, 94025-3493

    Carol E. Green & Charles A. Tyson

  4. Research and Development Division, Daiichi Pure Chemicals Co., LTD., 3-13-5 Nihombashi, Chuo-ku, Tokyo, 103, Japan

    Noriaki Shimada

  5. Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Yuichi Sugiyama

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  1. Shin-ichi Kanamitsu
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Kanamitsu, Si., Ito, K., Green, C.E. et al. Prediction of In Vivo Interaction Between Triazolam and Erythromycin Based on In Vitro Studies Using Human Liver Microsomes and Recombinant Human CYP3A4. Pharm Res 17, 419–426 (2000). https://doi.org/10.1023/A:1007572803027

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