Relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity after intravenous infusions of cisplatin to cancer patients |
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| Authors: | Naomi Nagai Masafumi Kinoshita H. Ogata Daijiro Tsujino Yuji Wada Kazuhiko Someya Tetsuro Ohno Keisou Masuhara Yoshio Tanaka Katsuhiko Kato Haruki Nagai Akira Yokoyama Yuzou Kurita |
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| Affiliation: | (1) Department of Biopharmaceutics, Meiji College of Pharmacy, Yato-cho 1-22-1, Tanashi-shi, Tokyo 188, Japan Fax 81-424-21-1489, JP;(2) Third Department of Internal Medicine, St. Marianna University, School of Medicine and Hospital, Sugao 2-16-1, Miyamae-ku, Kawasaki-shi, Kanagawa 213, Japan, JP;(3) Department of Pharmacy, St. Marianna University, School of Medicine and Hospital, Sugao 2-16-1, Miyamae-ku, Kawasaki-shi, Kanagawa 213, Japan, JP;(4) Department of Pharmacy, Niigata Cancer Center Hospital, Kawagishi-cho 2-15-3, Niigata-shi, Niigata 951, Japan, JP;(5) Department of Internal Medicine, Niigata Cancer Center Hospital, Kawagishi-cho 2-15-3, Niigata-shi, Niigata 951, Japan, JP |
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| Abstract: | Purpose: The relationships between pharmacokinetic parameters of unchanged cisplatin (CDDP) and several markers for nephrotoxicity after CDDP infusion (80 mg/m2) over 2 and 4 h were quantitated in patients with various cancers (lung, stomach and colon cancers and mediastinal tumor). Methods: Plasma and urinary levels of unchanged CDDP were measured using a specific high-performance liquid chromatography method. Pharmacokinetic parameters were calculated according to the model-independent method. The nephrotoxicity markers, blood urea nitrogen (BUN), serum creatinine (SCr), plasma and urinary β2-microglobulin (BMGp and BMGu), urinary N-acetyl-β-D-glucosaminidase (NAG) and creatinine clearance (CCR) were monitored for 30 days following CDDP administration. Results: The maximum plasma concentration (Cmax), maximum urinary excretion rate (dAe/dtmax), area under the plasma concentration-time curve from time zero to infinity (AUC), cumulative amount excreted in urine from time zero to infinity (Ae), total clearance (Clt), renal clearance (Clr) and plasma half-life (t1/2) of unchanged CDDP were not significantly different between the 2-h and 4-h infusion schedules. The values of the nephrotoxicity markers changed significantly following CDDP administration, suggesting that CDDP chemotherapy (80 mg/m2) caused nephrotoxicity. The Cmax of unchanged CDDP was the most informative pharmacokinetic parameter for nephrotoxicity. Cmax was related to maximum BUN, maximum SCr and minimum CCR levels in 27 CDDP treatments according to an exponential model. Conclusion: In order to attain more effective CDDP chemotherapy with minimum nephrotoxicity, the present pharmacokinetic and pharmacodynamic studies suggest that the Cmax or steady-state plasma level of unchanged CDDP should be maintained between 1.5 and 2 μg/ml in a standard continuous infusion schedule over 2 h and 4 h. Received: 2 May 1995/Accepted: 25 March 1996 |
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| Keywords: | Unchanged cisplatin Nephrotoxicity Pharmacokinetics Pharmacodynamics Maximum plasma concentration |
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