The disposition of 6-deoxyacyclovir, a xanthine oxidase-activated prodrug of acyclovir, in the isolated perfused rat liver

Authors

  • D. Brian Jones,

    1. Liver Diseases Section, National Institute of Diabetes, and Digestive and Kidney Diseases National Institutes of Health, Bethesda, Maryland 20892
    2. Department of Clinical Pharmacology, Johns Hopkins Hospital, Baltimore, Maryland 21205; and Burroughs Wellcome Company, Research Triangle, North Carolina 27709
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  • Vinod K. Rustgi,

    1. Liver Diseases Section, National Institute of Diabetes, and Digestive and Kidney Diseases National Institutes of Health, Bethesda, Maryland 20892
    2. Department of Clinical Pharmacology, Johns Hopkins Hospital, Baltimore, Maryland 21205; and Burroughs Wellcome Company, Research Triangle, North Carolina 27709
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  • David M. Kornhauser,

    1. Liver Diseases Section, National Institute of Diabetes, and Digestive and Kidney Diseases National Institutes of Health, Bethesda, Maryland 20892
    2. Department of Clinical Pharmacology, Johns Hopkins Hospital, Baltimore, Maryland 21205; and Burroughs Wellcome Company, Research Triangle, North Carolina 27709
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  • Amina Woods,

    1. Liver Diseases Section, National Institute of Diabetes, and Digestive and Kidney Diseases National Institutes of Health, Bethesda, Maryland 20892
    2. Department of Clinical Pharmacology, Johns Hopkins Hospital, Baltimore, Maryland 21205; and Burroughs Wellcome Company, Research Triangle, North Carolina 27709
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  • Richard Quinn,

    1. Liver Diseases Section, National Institute of Diabetes, and Digestive and Kidney Diseases National Institutes of Health, Bethesda, Maryland 20892
    2. Department of Clinical Pharmacology, Johns Hopkins Hospital, Baltimore, Maryland 21205; and Burroughs Wellcome Company, Research Triangle, North Carolina 27709
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  • Jay H. Hoofnagle,

    1. Liver Diseases Section, National Institute of Diabetes, and Digestive and Kidney Diseases National Institutes of Health, Bethesda, Maryland 20892
    2. Department of Clinical Pharmacology, Johns Hopkins Hospital, Baltimore, Maryland 21205; and Burroughs Wellcome Company, Research Triangle, North Carolina 27709
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  • E. Anthony Jones

    1. Liver Diseases Section, National Institute of Diabetes, and Digestive and Kidney Diseases National Institutes of Health, Bethesda, Maryland 20892
    2. Department of Clinical Pharmacology, Johns Hopkins Hospital, Baltimore, Maryland 21205; and Burroughs Wellcome Company, Research Triangle, North Carolina 27709
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Abstract

The antiviral drug, acyclovir, has been used in the treatment of chronic type B hepatitis. High serum concentrations of acyclovir are required to achieve inhibition of hepatitis B viral replication. Because only 15 to 20% of an oral dose is absorbed, it is necessary to administer acyclovir by intravenous infusion. 6-Deoxyacyclovir, an analog of acyclovir, is well absorbed when given orally, and is converted to acyclovir by xanthine oxidase which is present in the gut and liver. This study has examined the hepatic disposition of 6-deoxyacyclovir in a 100 ml recirculating (12 ml per min) perfused rat liver system. Following administration of a bolus dose of 5 μmoles 6-deoxyacyclovir to the reservoir, perfusate concentrations of 6-deoxyacyclovir declined monoexponentially, as the metabolite acyclovir appeared in the perfusate. Addition of the xanthine oxidase inhibitor allopurinol (5 mg) to the perfusate reservoir prior to the administration of 6-deoxyacyclovir resulted in impaired hepatic metabolism of 6-deoxyacyclovir, as demonstrated by a 47% reduction in systemic clearance rate (4.5 ± 0.4 to 2.4 ± 0.9 ml per min; p < 0.05) (mean ± S.E., n = 6) and a 1.8-fold increase in terminal elimination half-life of 6-deoxyacyclovir (23.5 ± 2.7 to 42.7 ± 4.1 min; p < 0.05), accompanied by a 30% reduction in appearance of acyclovir. The efficient hepatic conversion of 6-deoxyacyclovir to the active antiviral drug, acyclovir, provides a rationale for trials of oral 6-deoxyacyclovir in the treatment of chronic type B hepatitis.

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