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Research ArticleArticle

Dose-Dependent Pharmacokinetics of Cyclosporin A in Rats: Events in Tissues

Chiaki Tanaka, Ryosei Kawai and Malcolm Rowland
Drug Metabolism and Disposition May 2000, 28 (5) 582-589;
Chiaki Tanaka
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Ryosei Kawai
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Malcolm Rowland
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Abstract

Cyclosporin A (CyA) tissue distribution kinetics was extensively studied after single 1.2-, 6-, and 30-mg/kg CyA doses (via 2-min i.v. infusion) to rats. Drug concentrations in blood and various tissues were measured using a specific radioimmunoassay. Based on total blood concentration data alone, CyA systemic pharmacokinetics appeared essentially linear. However, after taking the saturable, nonlinear blood cell binding into account, multiple nonlinear factors were identified. Intrinsic clearance at 30 mg/kg was about half the value at the two lower doses. Tissue distribution was also dose-dependent, with evidence of saturable binding in many tissues. In general, blood binding saturation (dissociation constantKD = 0.18 μg/ml) occurred at a lower dose (concentration) than saturation of tissue binding (KD, 0.005–0.77 μg/g), such that the volume of distribution at steady state first increased as the dose increased from 1.2 to 6 mg/kg, and then decreased as the dose increased to 30 mg/kg. Tissue binding was further investigated by various graphical analyses. Some organs showed a monophasic (single site) Scatchard plot of the tissue data at steady state, with highKD values. In other organs, biphasic binding characteristics were observed with the KDvalues of the high-affinity site in the same range as theKD reported for the binding of CyA with cyclophilin, the putative target. Saturable tissue binding may therefore influence not only the pharmacokinetics but also the efficacy of CyA.

Footnotes

  • Send reprint requests to: Dr. Ryosei Kawai, Novartis Pharma AG, Drug Metabolism and Pharmacokinetics, K-135.1.19, CH-4002, Basel, Switzerland. E-mail:ryosei.kawai{at}pharma.novartis.com

  • Abbreviations used are::
    CyA
    cyclosporin A
    Vss
    volume of distribution at steady state
    CyPh
    cyclophilin
    PBPK
    physiologically based pharmacokinetic
    Cu
    unbound drug concentration in plasma water
    CP
    drug concentration in plasma
    fuP
    unbound fraction in plasma
    CB
    drug concentration in blood
    fuB
    unbound fraction in blood
    Hct
    hematocrit
    AUC
    area under the concentration-time curve
    CL
    systemic clearance
    CT
    tissue concentration
    Kp
    tissue-to-blood partition coefficient
    Kpu
    tissue-to-unbound-drug concentration partition coefficient
    Kpu,app
    tissue-to-unbound drug concentration ratios at each tissue sampling time
    RIA
    radioimmunoassay
    • Received November 11, 1999.
    • Accepted February 9, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (5)
Drug Metabolism and Disposition
Vol. 28, Issue 5
1 May 2000
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Research ArticleArticle

Dose-Dependent Pharmacokinetics of Cyclosporin A in Rats: Events in Tissues

Chiaki Tanaka, Ryosei Kawai and Malcolm Rowland
Drug Metabolism and Disposition May 1, 2000, 28 (5) 582-589;

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Research ArticleArticle

Dose-Dependent Pharmacokinetics of Cyclosporin A in Rats: Events in Tissues

Chiaki Tanaka, Ryosei Kawai and Malcolm Rowland
Drug Metabolism and Disposition May 1, 2000, 28 (5) 582-589;
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