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OtherRENAL PHARMACOLOGY

Disposition of Morphine in the Rat Isolated Perfused Kidney: Concentration Ranging Studies

Kathryn M. Shanahan, Allan M. Evans and Roger L. Nation
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1518-1525;
Kathryn M. Shanahan
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Allan M. Evans
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Roger L. Nation
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Abstract

The rat isolated perfused kidney was used to investigate the linearity of the renal disposition of morphine and its potential oxidative and glucuronidative metabolism by the kidney. In a set of single-dose experiments, morphine was administered to recirculating perfusion medium to achieve initial concentrations of 0.2, 2 and 20 μM (n = 4 at each concentration). In a set of multiple-dose experiments, morphine was administered to perfusate as sequential bolus doses to achieve concentrations of 0.2, 2, 20 and 200 μM (n = 6). HPLC was used to determine the concentration of morphine in perfusate and urine. Normorphine, morphine-3-glucuronide and morphine-6-glucuronide could not be detected in perfusate or urine, a result that suggests an absence of oxidative and glucuronidative metabolism of morphine by the rat kidney. The volume of distribution of morphine within the kidney was high (31 ± 3 ml/g at 0.2 μM), which indicates extensive accumulation, and remained constant with increasing perfusate concentration. The ratio of unbound renal excretory clearance to glomerular filtration rate was always greater than unity for all kidneys, which indicates that the renal excretion of morphine involves net tubular secretion. This ratio was constant (P > .05) over the 100-fold concentration range of the single-dose study. In the multiple-dose study, the ratio was marginally but significantly (P < .05) higher at concentrations of 2, 20 and 200 μM than at 0.2 μM, a difference that cannot be explained by saturation of tubular secretion. The results suggest that the tubular secretion of morphine is not saturated over a wide range of concentrations (0.2–200 μM).

Footnotes

  • Send reprint requests to: Dr. Allan M. Evans, Centre for Pharmaceutical Research, School of Pharmacy and Medical Sciences, University of South Australia, GPO Box 2471 Adelaide, South Australia, 5001.

  • ↵1 This study was supported by the National Health and Medical Research Council of Australia, grant number 940330.

  • Abbreviations:
    Ae090
    total amount of morphine excreted unchanged in urine between 0 and 90 min
    AUC090
    area under the perfusate morphine concentrationvs. time curve from 0 to 90 min
    AUC0∞
    area under the perfusate morphine concentration vs. time curve from time zero to infinity
    BSA
    bovine serum albumin
    CLM
    total organ clearance of morphine
    CLRM
    renal excretory clearance of morphine in a urine collection interval
    CLR(0–90)M
    renal excretory clearance of morphine from 0 to 90 min
    fu
    fraction of morphine unbound in perfusate
    IPK
    isolated perfused kidney
    M3G
    morphine-3-glucuronide
    M6G
    morphine-6-glucuronide
    %TR
    percent tubular reabsorption
    T1/2
    half-life
    UFR
    urine flow rate
    VKM
    volume of distribution of morphine within the kidney
    Vp
    perfusate volume
    • Received November 18, 1996.
    • Accepted May 6, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherRENAL PHARMACOLOGY

Disposition of Morphine in the Rat Isolated Perfused Kidney: Concentration Ranging Studies

Kathryn M. Shanahan, Allan M. Evans and Roger L. Nation
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1518-1525;

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OtherRENAL PHARMACOLOGY

Disposition of Morphine in the Rat Isolated Perfused Kidney: Concentration Ranging Studies

Kathryn M. Shanahan, Allan M. Evans and Roger L. Nation
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1518-1525;
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