Example 1
CYP-enzyme phenotyping using human liver microsomes and recombinant CYP enzymes revealed that mitapivat sulfate was primarily metabolized by CYP3A4/5 (>90%), with minor contributions from CYP2C9, CYP2C8, and CYP1A2. There was evidence of metabolism-dependent inhibition of CYP2C19 (largely reversible) and CYP3A4 (largely irreversible). Mitapivat sulfate was found to be a substrate and inhibitor for P-gp but not for breast cancer resistance protein (BCRP) and was found to be a potential inducer of human CYP2B6 and CYP3A4. Mitapivat sulfate appeared to be a mild inhibitor of CYP2C8, CYP2C9, xYP2C19, CYP2D6, and CYP3A4/5 enzymes (testosterone 6β-hydroxylation), bile salts export pump (BSEP), organic anion transporting polypeptide (OATP)1B1, organic anion transporter (OAT)3, and organic cation transporter (OCT)2, and of uridine-5′-diphospho-glucuronosyltransferase (UGT) 1A3, 1A4, and 1A9. Mitapivat sulfate does not appear to be an inhibitor of multidrug resistance-associated protein (MRP)2, MRP3, OATP1B3, and OAT1. The metabolite was found to be a mild inhibitor of CYP2C9 and CYP2C19 and was not an inhibitor of P-gp or BCRP under tested concentrations.
