Effect of severe renal dysfunction on the pharmacokinetics of DNA-reactive platinum after oxaliplatin administration

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Effect of severe renal dysfunction on the pharmacokinetics of DNA-reactive platinum after oxaliplatin administration

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Co-author 1

Shunsaku Nakagawa nakashun@kuhp.kyoto-u.ac.jp Kyoto University Hospital Department of Clinical Pharmacology and Therapeutics Kyoto Japan *

Co-author 2

Aimi Shimazaki nakashun@kuhp.kyoto-u.ac.jp Kyoto University Hospital Department of Clinical Pharmacology and Therapeutics Kyoto Japan -

Co-author 3

Taro Funakoshi nakashun@kuhp.kyoto-u.ac.jp Graduate School of Medicine, Kyoto University Department of Therapeutic Oncology Kyoto Japan -

Co-author 4

Atsushi Yonezawa nakashun@kuhp.kyoto-u.ac.jp Faculty of Pharmacy, Keio University Division of Integrative Clinical Pharmacology Tokyo Japan -

Co-author 5

Shigeki Kataoka nakashun@kuhp.kyoto-u.ac.jp Graduate School of Medicine, Kyoto University Department of Therapeutic Oncology Kyoto Japan -

Co-author 6

Takahiro Horimatsu nakashun@kuhp.kyoto-u.ac.jp Graduate School of Medicine, Kyoto University Department of Therapeutic Oncology Kyoto Japan -

Co-author 7

Daiki Hira nakashun@kuhp.kyoto-u.ac.jp Kyoto University Hospital Department of Clinical Pharmacology and Therapeutics Kyoto Japan -

Co-author 8

Kotaro Itohara nakashun@kuhp.kyoto-u.ac.jp Kobe University Hospital Department of Pharmacy Kobe Japan -

Co-author 9

Satoshi Imai nakashun@kuhp.kyoto-u.ac.jp School of Pharmaceutical Sciences, Wakayama Medical University Department of Medical Neuropharmacology Wakayama Japan -

Co-author 10

Takayuki Nakagawa nakashun@kuhp.kyoto-u.ac.jp School of Pharmaceutical Sciences, Wakayama Medical University Department of Clinical Pharmacology and Pharmacotherapy Wakayama Japan -

Co-author 11

Takeshi Matsubara nakashun@kuhp.kyoto-u.ac.jp Tazuke Kofukai Medical Research Institute and Kitano Hospital Department of Nephrology Kyoto Japan -

Co-author 12

Motoko Yanagita nakashun@kuhp.kyoto-u.ac.jp Kyoto University Graduate School of Medicine Department of Nephrology Osaka Japan -

Co-author 13

Manabu Muto nakashun@kuhp.kyoto-u.ac.jp Graduate School of Medicine, Kyoto University Department of Therapeutic Oncology Kyoto Japan -

Co-author 14

Kazuo Matsubara nakashun@kuhp.kyoto-u.ac.jp Wakayama Medical University School of Pharmaceutical Sciences Wakayama Japan -

Co-author 15

Tomohiro Terada nakashun@kuhp.kyoto-u.ac.jp Kyoto University Hospital Department of Clinical Pharmacology and Therapeutics Kyoto Japan -

Introduction

Higher amounts of circulating ultrafilterable platinum (fPt) are found in patients with renal dysfunction receiving a constant dose of oxaliplatin. However, it has been suggested that the increased systemic exposure of fPt do not increase oxaliplatin-induced toxicities. We hypothesized that the kidney has minimal effect on the elimination rate of reactive fPt. In this study, we aimed to quantify DNA-reactive fPt in plasma and to evaluate the impact of severe renal dysfunction on its pharmacokinetics.

Methods

The pharmacokinetics of Pt after the administration of oxaliplatin was assessed in rats with bilateral nephrectomy (BNx) and in a patient with hemodialysis who received mFOLFOX7 therapy for advanced metastatic gastric cancer. The Pt concentrations were determined using inductively coupled plasma-mass spectrometry.
The amount of DNA-reactive fPt in the plasma was evaluated by the reaction between plasma and calf thymus DNA.

Results

Compared to the sham group in rats, the BNx group had significantly higher plasma total fPt concentrations at 24 h after oxaliplatin administration. However, there was no significant difference in the plasma levels of DNA-reactive fPt between the two groups. In a hemodialysis patient, the plasma levels of total fPt decreased to 36 and 7% at 2 and 14 d after the administration, respectively. The plasma level of DNA-reactive fPt also decreased to 2 and 1%, respectively, on these durations.

Conclusion

In this study, we showed that the kidney has a limited effect on the plasma levels of DNA-reactive fPt after oxaliplatin administration.

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