Using population pharmacokinetic analyses of drugs metabolized by CYP2D6 to study the genotype–phenotype translation

Abstract

Cytochrome P450 2D6 (CYP2D6) is an important drug-metabolizing enzyme exhibiting extensive interindividual variability predominantly caused by genetic polymorphism. Predicting CYP2D6 function based on genotype may be used to personalize pharmacotherapy, but the process of translating CYP2D6 genotype into predicted phenotype is complex and has suffered from a lack of consensus. The Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group have proposed a standardized translation scheme based on the activity score system aiming to facilitate more consistent CYP2D6 genotype-phenotype translation. However, this system remains suboptimal particularly with regards to decreased function alleles and substrate-specific behaviour. This review summarizes the process and challenges for functional assignment of CYP2D6 alleles. We discuss population pharmacokinetics (popPK) as a tool for estimating CYP2D6 function and present findings from three popPK meta-analyses quantifying the impact of individual CYP2D6 alleles in the metabolism of vortioxetine, tedatioxetine and brexpiprazole. Findings from these analyses indicate that the activity values currently assigned to decreased function alleles CYP2D6*9, *17 and *41 overestimate their function. Moreover, the CYP2D6*2 allele exhibited reduced activity in the metabolism of brexpiprazole, indicating substrate-specific behaviour.Considering the totality of the evidence, the activity score system may be further refined to better reflect the enzyme function associated with these alleles.

Mechanism-Based Inactivation of CYP2D6 by Phellopterin and Related Drug–Drug Interaction with Metoprolol

“…Despite accounting for only 2−4% of the whole P450 family, 13 the enzyme is reportedly in charge of the metabolism of about 20% of routinely used medicinal agents. 14 Several types of drugs, including analgesics, antidepressants, and antihypertensives, may be metabolized by CYP2D6. 15 Metoprolol, a selective β1 receptor blocker, is widely used in clinical practice for the treatment of hypertension, angina, and heart failure.…”

“…The CYP2D6 subtype is an important member of the P450 enzyme family. Despite accounting for only 2–4% of the whole P450 family, the enzyme is reportedly in charge of the metabolism of about 20% of routinely used medicinal agents . Several types of drugs, including analgesics, antidepressants, and antihypertensives, may be metabolized by CYP2D6 …”

Interactions of coreopsin with CYP3A4/CYP2D6 by multi-spectroscopy analysis and computer simulation

“…CYP2D6 is also critical metabolism enzyme since it can partake in over 20% of drugs metabolism [11]. Moreover, CYP2D6 exhibits extensive inter-individual variability, resulting in considerable differences in drug exposure [12]. Some drugs metabolized by CYP2D6 usually have a narrow therapeutic window, thus resulting overexposure or poor drug response [13].…”

Gender balance in the editorial room: BCPT as model journal?

“…With respect to the Young Investigator Award, there is a 50:50 gender balance in the recipients. [7][8][9][10] Unfortunately, the Young Researcher Nordic Prize (established in 2020) has yet to be awarded to a woman. 11,12 Moreover, only a single female has ever been nominated (and that was as late as in 2020).…”