RT Journal Article
SR Electronic
T1 Low Potential of Basimglurant to Be Involved in Drug-Drug Interactions: Influence of Non–Michaelis-Menten P450 Kinetics on Fraction Metabolized
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 164
OP 173
DO 10.1124/jpet.116.237214
VO 360
IS 1
A1 Fowler, Stephen
A1 Guerini, Elena
A1 Qiu, NaHong
A1 Cleary, Yumi
A1 Parrott, Neil
A1 Greig, Gerard
A1 Mallalieu, Navita L.
YR 2017
UL http://jpet.aspetjournals.org/content/360/1/164.abstract
AB Basimglurant, a novel mGlu5-negative allosteric modulator under development for the treatment of major depressive disorder, is cleared via cytochrome P450 (P450)-mediated oxidative metabolism. Initial enzyme phenotyping studies indicated that CYP3A4/5 dominates basimglurant metabolism and highlights a risk for drug-drug interactions when it is comedicated with strong CYP3A4/5 inhibitors or inactivators; however, a clinical drug-drug interaction (DDI) study using the potent and selective CYP3A4/5 inhibitor ketoconazole resulted in an area under the curve (AUC) AUCi/AUC ratio of only 1.24. A further study using the CYP3A4 inducer carbamazepine resulted in an AUCi/AUC ratio of 0.69. More detailed in vitro enzyme phenotyping and kinetics studies showed that, at the low concentrations attained clinically, basimglurant metabolic clearance is catalyzed mainly by CYP1A2. The relative contributions of the enzymes were estimated as 70:30 CYP1A2:CYP3A4/5. Using this information, a clinical study using the CYP1A2 inhibitor fluvoxamine was performed, resulting in an AUCi/AUC ratio of 1.60, confirming the role of CYP1A2 and indicating a balanced DDI risk profile. Basimglurant metabolism kinetics show enzyme dependency: CYP1A2-mediated metabolism follows Michaelis-Menten kinetics, whereas CYP3A4 and CYP3A5 follow sigmoidal kinetics [with similar constant (KM) and S50 values]. The interplay of the different enzyme kinetics leads to changing fractional enzyme contributions to metabolism with substrate concentration, even though none of the metabolic enzymes is saturated. This example demonstrates the relevance of non–Michaelis-Menten P450 enzyme kinetics and highlights the need for a thorough understanding of metabolism enzymology to make accurate predictions for human metabolism in vivo.