title: In vitro glucuronidation of aprepitant: a moderate inhibitor of UGT2B7.
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 µM, 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 ∼10 µM 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.
authors.affiliation: a Department of Medicine , University of Chicago , Chicago , IL , USA.
authors.forename: Larry
authors.initials: L
authors.lastname: House
authors.affiliation: a Department of Medicine , University of Chicago , Chicago , IL , USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ramirez
authors.affiliation: a Department of Medicine , University of Chicago , Chicago , IL , USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Seminerio
authors.affiliation: a Department of Medicine , University of Chicago , Chicago , IL , USA.
authors.forename: Snezana
authors.initials: S
authors.lastname: Mirkov
authors.affiliation: a Department of Medicine , University of Chicago , Chicago , IL , USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000077608:Aprepitant; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D009025:Morpholines / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D009025:Morpholines; D000077608:Aprepitant; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase
keywords: Aprepitant; drug metabolism; phase II