Key result
Analysis of 13 CYP2D6 and 18 CYP3A4/5 model drugs showed that chronic kidney disease severity decreased CYP2D6-mediated clearance, with no apparent effect on CYP3A4/5-mediated clearance.
Why the study?
Does chronic kidney disease affect the pharmacokinetics of CYP2D6- and CYP3A4/5-metabolized drugs?
Systematic Review
Does chronic kidney disease affect the pharmacokinetics of CYP2D6- and CYP3A4/5-metabolized drugs?
CKD severity decreases CYP2D6-mediated clearance but does not affect CYP3A4/5-mediated clearance, highlighting the need for specific clinical CKD studies for nonrenally eliminated drugs.
Suggests caution with CYP2D6 substrates in CKD; extends evidence on differential CYP effects in renal impairment.
Recent reviews suggest that chronic kidney disease (CKD) can affect the pharmacokinetics of nonrenally eliminated drugs, but the impact of CKD on individual elimination pathways has not been systematically evaluated. In this study we developed a comprehensive dataset of the effect of CKD on the pharmacokinetics of CYP2D6- and CYP3A4/5-metabolized drugs. Drugs for evaluation were selected based on clinical drug-drug interaction (CYP3A4/5 and CYP2D6) and pharmacogenetic (CYP2D6) studies. Information from dedicated CKD studies was available for 13 and 18 of the CYP2D6 and CYP3A4/5 model drugs, respectively. Analysis of these data suggested that CYP2D6-mediated clearance is generally decreased in parallel with the severity of CKD. There was no apparent relationship between the severity of CKD and CYP3A4/5-mediated clearance. The observed elimination-route dependency in CKD effects between CYP2D6 and CYP3A4/5 may inform the need to conduct clinical CKD studies with nonrenally eliminated drugs for optimal use of drugs in patients with CKD.
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Yoshida et al. (2016) conducted a systematic review in Chronic kidney disease. Chronic kidney disease vs. No CKD or lower severity of CKD was evaluated on CYP2D6- and CYP3A4/5-mediated clearance. Analysis of 13 CYP2D6 and 18 CYP3A4/5 model drugs showed that chronic kidney disease severity decreased CYP2D6-mediated clearance, with no apparent effect on CYP3A4/5-mediated clearance.
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