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 mumoles
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 less than 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 less than 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.