In vitro glucuronidation of aprepitant: a moderate inhibitor of UGT2B7.

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House L, Ramirez J, Seminerio M, Mirkov S, Ratain MJ

In vitro glucuronidation of aprepitant: a moderate inhibitor of UGT2B7.

Xenobiotica. 2015;45(11):990-8. doi: 10.3109/00498254.2015.1038743. Epub 2015 Jun 8.

PubMed ID

26053558 [ View in PubMed

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Abstract

1. Aprepitant, an oral antiemetic, commonly used in the prevention of chemotherapy-induced nausea and vomiting, is primarily metabolized by CYP3A4. Aprepitant glucuronidation has yet to be evaluated in humans. The contribution of human UDP-glucuronosyltransferase (UGT) isoforms to the metabolism of aprepitant was investigated by performing kinetic studies, inhibition studies and correlation analyses. In addition, aprepitant was evaluated as an inhibitor of UGTs. 2. Glucuronidation of aprepitant was catalyzed by UGT1A4 (82%), UGT1A3 (12%) and UGT1A8 (6%) and Kms were 161.6 +/- 15.6, 69.4 +/- 1.9 and 197.1 +/- 28.2 microM, respectively. Aprepitant glucuronidation was significantly correlated with both UGT1A4 substrates anastrazole and imipramine (rs = 0.77, p < 0.0001 for both substrates; n = 44), and with the UGT1A3 substrate thyroxine (rs = 0.58, p < 0.0001; n = 44). 3. We found aprepitant to be a moderate inhibitor of UGT2B7 with a Ki of approximately 10 microM for 4-MU, morphine and zidovudine. Our results suggest that aprepitant can alter clearance of drugs primarily eliminated by UGT2B7. Given the likelihood for first-pass metabolism by intestinal UGT2B7, this is of particular concern for oral aprepitant co-administered with oral substrates of UGT2B7, such as zidovudine and morphine.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Aprepitant	Cytochrome P450 2C19	Protein	Humans	Unknown	Substrate Inhibitor	Details