A change in a probe drug’s metabolism can have several mechanistic explanations. A 2018 metoprolol study investigated an apparent inconsistency by combining human pharmacokinetic observations with experiments in liver cells, microsomes, and recombinant enzymes.
After rifampicin treatment, data from 15 healthy volunteers showed a 25% increase in metoprolol clearance. Formation of alpha-hydroxymetoprolol increased by 9%, a statistically nonsignificant change. The observation raised a question about whether CYP2D6 itself had been induced or other pathways contributed.
Rifampicin increased CYP3A4 messenger RNA in two liver-cell systems while leaving CYP2D6 messenger RNA unaffected. Other experiments demonstrated that enzymes including CYP3A4, CYP2B6, and CYP2C9 could contribute to metoprolol metabolism. In microsomal inhibition experiments, their combined contribution to alpha-hydroxylation was approximately 4%.
The authors considered the additional contribution too small to compromise use of metoprolol alpha-hydroxylation for CYP2D6 phenotyping. That conclusion concerns the specific pathway and experimental evidence. Metoprolol’s other metabolic pathways had different contributions from additional enzymes. An expert interpreting a parent-to-metabolite ratio should identify which pathway the ratio represents, concurrent enzyme-modifying drugs, and the supporting population. A change in an observed ratio alone leaves the responsible mechanism open to investigation.
Read the full scientific paper. DOI 10.3389/fphar.2018.00774.