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Decreased Disposition of Anticancer Drugs Predominantly Eliminated via the Liver in Patients with Renal Failure

[ Vol. 20 , Issue. 5 ]

Author(s):

Ken-ichi Fujita *, Natsumi Matsumoto, Hiroo Ishida, Yutaro Kubota, Shinichi Iwai, Motoko Shibanuma and Yukio Kato   Pages 361 - 376 ( 16 )

Abstract:


Background: Evidence has revealed that renal impairment can affect the systemic exposure of drugs which are predominantly eliminated via the liver. The modulation of drug-metabolizing enzymes and transporters expressed in the liver and/or small intestine by diverse entities, including uremic toxins, in systemic circulation of patients with severe renal failure is considered as the cause of atypical pharmacokinetics, which sometimes induce undesirable adverse events that are especially critical for drugs with narrow therapeutic window such as anticancer drugs. A dosing strategy for anticancer drugs in these patients needs to be established.

Methods: The effects of renal impairment on the systemic exposure and safety of anticancer drugs were summarized. The proposed mechanisms for the alterations in the pharmacokinetics of these anticancer drugs were also discussed.

Results: Changes in pharmacokinetics and clinical response were reported in 9 out of 10 cytotoxic anticancer drugs investigated, although available information was limited and sometimes controversial. Systemic exposure of 3 out of 16 tyrosine kinase inhibitors was higher in patients with severe renal failure than that in patients with normal kidney function. An increase in systemic exposure of anticancer drugs in patients with renal impairment is likely to be observed for substrates of OATP1B1, despite the limited evidence.

Conclusion: The molecular basis for the effect of uremia on non-renal drug elimination still needed to be clarified with further studies to generate generalizable concepts, which may provide insights into establishing better clinical usage of anticancer drugs, i.e. identifying patients at risk and dose adjustment.

Keywords:

Renal failure, cytotoxic anticancer drug, tyrosine kinase inhibitor, non-renal clearance, systemic exposure, drug-metabolizing enzyme, transporter, organic-anion transporting polypeptide 1B1.

Affiliation:

Division of Cancer Cell Biology, Department of Pharmaceutical Sciences, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 1428555, Department of Healthcare and Regulatory Sciences, Showa University School of Pharmacy, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo 1428555, Department of Medical Oncology, Showa University School of Medicine, 1-5- 8 Hatanodai, Shinagawa-ku, Tokyo 1428555, Department of Medical Oncology, Showa University School of Medicine, 1-5- 8 Hatanodai, Shinagawa-ku, Tokyo 1428555, Department of Healthcare and Regulatory Sciences, Showa University School of Pharmacy, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo 1428555, Division of Cancer Cell Biology, Department of Pharmaceutical Sciences, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 1428555, Molecular Pharmacotherapeutics, Faculty of Pharmacy, Kanazawa University, Kakuma-machi, Kanazawa 9201192

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