Effect of Chronic Kidney Disease on Nonrenal Elimination Pathways: A Systematic Assessment of CYP1A2, CYP2C8, CYP2C9, CYP2C19, and OATP

Abstract

Our recent studies have shown that chronic kidney disease (CKD) affects the pharmacokinetics (PKs) of cytochrome P450 (CYP)2D6-metabolized drugs, whereas effects were less evident on CYP3A4/5. Therefore, the effect of CKD on the disposition of CYP1A2-metabolized, CYP2C8-metabolized, CYP2C9-metabolized, CYP2C19-metabolized, and organic anion-transporting polypeptide (OATP)-transported drugs was investigated. We identified dedicated CKD studies with 6, 5, 6, 4, and 12 "model" substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, and OATP, respectively. Our analyses suggest that clearance of OATP substrates decreases as kidney function declines. Similar trends were seen for CYP2C8; but overlap between some CYP2C8 and OATP substrates highlights that their interplay needs further investigation. In contrast, the effect of CKD on CYP1A2, CYP2C9, and CYP2C19 was variable and modest compared to CYP2C8 and OATP. This improved understanding of elimination-pathway-dependency in CKD is important to inform the need and conduct of PK studies in these patients for nonrenally eliminated drugs.

Figure 1

Overview of the workflow of clinical chronic kidney disease (CKD) data collection for cytochrome P450 (CYP)1A2, CYP2C8, CYP2C9, CYP2C19, and organic anion transporting polypeptide (OATP) model substrate drugs. AUCR, area under the concentration‐time curve ratio; DDI, drug‐drug interaction; DIDB, The University of Washington Metabolism and Transport Drug Interaction Database; f_e,urine, fraction of the dose eliminated into urine unchanged; PGx, pharmacogenetics; USFDA, US Food and Drug Administration.

Figure 2

Comparison of observed clearance ratio (R_CL) and theoretical lowest R_CL without changes in nonrenal clearance for cytochrome P450 (CYP)1A2 (a), CYP2C8 (b), CYP2C9 (c), CYP2C19 (d), and organic anion transporting polypeptide (OATP) (e) model substrate drugs. Symbols represent R_CL_unbound in each chronic kidney disease (CKD) group of a clinical CKD study for drugs with protein binding information in healthy control and CKD groups, or R_CL_total for all drugs, including those without protein binding information in CKD studies. Solid red lines represent the theoretical lowest ratio assuming no changes in nonrenal clearance (the values are 0.88, 0.79, 0.73, and 0.69 for the mild CKD, moderate CKD, severe CKD, and the endstage renal disease (ESRD) patient groups, respectively). ^aEstimated unbound clearance ratios based on averaged plasma albumin level change for OATP/CYP2C8 model drugs missing protein binding information for severe patients. See Methods section for details. R_CL_unbound, unbound clearance ratio between CKD patient groups and the healthy control group; R_CL_total, ratio of clearance calculated with total (bound plus unbound) concentration between CKD groups and the healthy control group. *Drugs with 2 ≤ AUCR <3. **Drugs f_u ≥ 0.3.

Figure 3

Effect of chronic kidney disease (CKD) on cytochrome P450 (CYP)1A2 (a), CYP2C8 (b), CYP2C9 (c), CYP2C19 (d) and organic anion transporting polypeptide (OATP) (e) model substrate drugs. The box‐and‐whisker plots represent interquartile range of unbound clearance ratio between CKD patient groups and the healthy control group (R_CL_unbound) for drugs with protein binding information, or total clearance ratio between CKD patient groups and the healthy control group (R_CL_total) for all drugs with CKD studies. The “+” symbols represents the mean value of R_CL, and red lines represent the theoretical lowest ratio assuming no CKD effect on nonrenal clearance (the values are 0.88, 0.79, 0.73, and 0.69 for the mild CKD, moderate CKD, severe CKD, and the endstage renal disease (ESRD) groups, respectively). n, number of CKD studies in each group.

Figure 4

Observed chronic kidney disease (CKD) effect on the plasma unbound fraction f_u ratio (CKD groups with respect to healthy control) for cytochrome P450 (CYP)1A2 (⋄), CYP2C8 (Δ), CYP2C9 (□), CYP2C19 (○), CYP2D6 (▽), CYP3A (+), and organic anion transporting polypeptide (OATP) (*) model substrate drugs. (a) Symbols represent observed f_u ratios, dashed lines represent the average of the model drugs for each CYP enzyme and transporter, and solid lines represent the averaged f_u ratios from all the model drugs investigated. (b) The box‐and‐whisker plots represent interquartile range of f_u ratios. (c) Unbound fraction ratios increase with CKD for drugs with the relatively low f_u (f_u < 0.01) vs. relatively high f_u (f_u ≥ 0.01). The 2D6 and 3A model drugs from a previous study22 were also included. ESRD, endstage renal disease; fu, unbound fraction; HC, healthy control; n, number of CKD studies in each category; f_u ratio, ratio of f_u between CKD groups and the healthy control group.