Inhibition of Theophylline Metabolism by Aciclovir.

Abstract

We report a case of side effects caused by the increase in plasma theophylline concentration after coadministration of aciclovir had been started during theophylline therapy. Interaction between theophylline and aciclovir has not previously been reported. Therefore, a study of the pharmacokinetic and metabolic interactions between theophylline and aciclovir was carried out in five healthy male volunteers. All subjects received a single oral dose of 320 mg theophylline (aminophylline, 400 mg) after they had taken oral aciclovir 800 mg five times daily for two consecutive days. The area under the curve from 0 to infinity of theophylline (AUC0-infinity) after coadministration of aciclovir was increased from 189.9 +/- 18.2 to 274.9 +/- 34.3 micrograms.h/ml (p < 0.01), and total body clearance was decreased from 28.4 +/- 2.9 to 19.8 +/- 2.5 ml/h/kg (p < 0.01). Further, there was a significant increase in urinary theophylline and decreases in urinary 1,3-dimethyluric acid and 1-methyluric acid after coadministration of aciclovir. The decrease in total body clearance is likely to have resulted from inhibition of metabolism via the oxidation pathway. The results indicated that with aciclovir therapy lower doses of theophylline might be necessary and careful monitoring of plasma concentrations was essential.

Lack of Effect of Aciclovir on Metabolism of Theophylline and Expression of Hepatic Cytochrome P450 1A2 in Rats

“…Effect of Single Intravenous Injection of Aciclovir on Pharmacokinetic Parameters of 1-Methyl-3-propylxanthine in Rats administered is also recovered in the urine as an unchanged form. 18) In spite of the fact that most of the administered aciclovir is not metabolized in animals and humans, the inhibitory effect of aciclovir against theophylline metabolism has been reported by Maeda et al, 23) who reported that total body clearance of theophylline and the formation clearance of its major metabolites, 1-methyluric acid, 3-methylxanthine and 1,3-dimethyluric acid from theophylline, decreased in healthy male volunteers who received oral aciclovir 800 mg five times daily for 2 d. They proposed that this mechanism is due to inhibition of CYP1A2-mediated theophylline metabolism by aciclovir. Therefore, there is a possibility that aciclovir modifies the pharmacokinetics of several drugs, including caffeine, 39,40) phenacetin 39,41) clozapine 42) and propranolol, 43) which are typical substrates for CYP1A2, and induces side effects.…”

“…In the present study, we chose intravenous and intraperitoneal injections as a dosing route of aciclovir, and the dose was chosen on the basis of clinical studies reported by Maeda and colleagues. 23) Then, to clarify the mechanism of drug interaction between theophylline and aciclovir, we examined the effect of aciclovir on the pharmacokinetics and metabolism of theophylline by a single intravenous injection of aciclovir (50 mg/kg) and multiple intraperitoneal injections of aciclovir (25 mg/kg twice a day for 3 d). The values of the pharmacokinetic parameters and urinary recovery of theophylline and its metabolites observed in control rats were comparable to those of our previous studies.…”

“…23) The discrepancy between results in rats and humans might be explained by differential selectivity and an affinity of aciclovir for CYP1A2 between rats and humans. For example, Eagling et al 47) reported that the inhibitory potency of furafylline, which is a potent selective inhibitor of CYP1A2 in humans against phenacetin O-deethylation, is 20-fold stronger in human liver microsomes (IC 50 ϭ0.48 mM) than that in rat liver microsomes (IC 50 ϭ20.8 mM), which might be due to differences in the structure of CYP1A2 protein between rats and humans.…”

“…18,19) Drug interaction between aciclovir and concomitantly administered drugs, such as cimetidine, probenecid and mycophenolate that are primarily excreted into the urine has been reported. [20][21][22] However, there is an interesting clinical report indicating that total body clearance of theophylline is decreased by multiple oral administrations of aciclovir (800 mg five times daily for two consecutive days) in healthy volunteers, 23) although theophylline is extensively metabolized in the liver. They proposed that the mechanism responsible for the decreases in theophylline clearance by coadministration of aciclovir might be due to inhibition of CYP1A2-mediated theophylline metabolism.…”