Several lines of emerging evidence indicate that kidney disease differentially affects uptake and efflux transporters and metabolic enzymes in the liver and gastrointestinal (GI) tract, and uremic toxins have been implicated as the cause. In patients with kidney disease, even drugs that are eliminated by nonrenal transport and metabolism could lead to important unintended consequences if they are administered without dose adjustment for reduced renal function. This is particularly so in the case of drugs with narrow therapeutic windows and may translate into clinically significant variations in exposure and response.

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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BACKGROUND Altered drug metabolism has been demonstrated in patients with end‐stage renal disease (ESRD). The aim of this study was to evaluate the acute effect of hemodialysis (HD) on CYP3A4 activity. METHODS 12 ESRD patients undergoing chronic HD and 12 matched control subjects participated. Hepatic CYP3A4 activity was assessed using the 14C‐erythromycin breath test (EBT). The EBT was administered two hours pre‐ and repeated two hours post‐hemodialysis and once in controls. Breath samples were collected at baseline and various time points up to 120 min after dosing, and then analyzed for 14C using scintillation counting. The traditional 20‐min flux measure and the novel 1/Tmax parameter were determined. RESULTS The flux of 14CO2 at the 20‐minute time point, expressed as the % of the administered dose exhaled per hour, increased by 27% post‐dialysis, from 2.34±0.8 to 2.98±1.04 (p<0.05). Pre‐ and post‐HD values were similar to those observed in control subjects (2.70±0.59; p=NS). Pre‐ and post‐HD 1/Tmax values approached but did not achieve a statistically significance difference (0.056±0.01 and 0.067±0.02, respectively, p=0.07). Pre‐HD 1/Tmax was lower than control (0.064±0.01, p<0.05) and normalized after dialysis. CONCLUSIONS These results suggest that hemodialysis acutely improves hepatic CYP3A4 activity and indicate that increased diligence is warranted when prescribing CYP3A substrates to ESRD patients. Clinical Pharmacology & Therapeutics (2005) 79, P23–P23; doi: