Importance of cytochrome P-450IIIA activity in determining dosage and blood levels of FK 506 and cyclosporine in liver transplant recipients

Authors

  • Yilmaz Cakaloglu,

    1. Institute of Liver Studies, King's College Hospital and King's College School of Medicine and Dentistry, London SE5 9PJ, United Kingdom
    Current affiliation:
    1. Istanbul Medical Faculty, Department of Gastroenterohepatology, Topkapi 34390, Istanbul, Turkey
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  • J. Michael Tredger PhD,

    Corresponding author
    1. Institute of Liver Studies, King's College Hospital and King's College School of Medicine and Dentistry, London SE5 9PJ, United Kingdom
    • Institute of Liver Studies, King's College School of Medicine and Dentistry, Bessemer Road, London SE5 9PJ, U.K
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  • John Devlin,

    1. Institute of Liver Studies, King's College Hospital and King's College School of Medicine and Dentistry, London SE5 9PJ, United Kingdom
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  • Roger Williams

    1. Institute of Liver Studies, King's College Hospital and King's College School of Medicine and Dentistry, London SE5 9PJ, United Kingdom
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Abstract

We have investigated the importance of cytochrome P-450IIIA enzyme activity in influencing dosage of the immunosuppressive drugs FK 506 and cyclosporine after liver transplantation. Cytochrome P-450IIIA enzyme activity in vivo was measured 1 yr postoperatively in 37 stable orthotopic liver graft recipients (21 receiving FK 506 and 16 given cyclosporine) by the erythromycin breath test and the production of monoethylglycinexylidide from lignocaine. A strong correlation existed between FK 506 dose and erythromycin breath test results (r=0.583, p<0.007), but no corresponding relationship with monoethylglycinexylidide production was observed. The FK 506 dose (14 to 196 μg/kg/day) also correlated closely with circulating predose levels of the drug in both plasma and blood (r=0.538 and 0.731, p=0.015 and<0.001, respectively). Although no correlation existed between cyclosporine dose (0.254 to 0.494 mg/kg/day) and trough blood levels, a relationship was demonstrated when erythromycin breath test results were included in the derived equation: Drug dose/cytochrome P-450IIIA activity ∝ drug level (p=0.011 vs. 0.175 without erythromycin breath test). A corresponding enhancement was demonstrated with erythromycin breath test results to relate FK 506 dose and plasma levels (p=0.006 versus 0.015 without erythromycin breath test results), although breath test results and FK 506 levels were highly discordant (p>0.8). The use of monoethylglycinexylidide test results as an alternative measure of cytochrome P-450IIIA activity provided no comparable increase in correlation for FK 506 or cyclosporine. Dissimilar dependencies on blood flow and gender may underlie the contrasting predictive value of the monoethylglycinexylidide and erythromycin breath test results, but the latter may be valuable in predicting FK 506 dosage in organ graft recipients and in relating cyclosporine dose and blood levels. (Hepatology 1994;20:309–316.)

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