Effects of probenecid on the pharmacokinetics and elimination of acyclovir in humans

Abstract

The effects of probenecid on the pharmacokinetics and renal clearance of acyclovir were studied in humans. Acyclovir (5 mg/kg) was given as a 1-h infusion to three volunteers with normal renal function both before and after oral administration of probenecid (1 g). The kinetics were well described by a twocompartment open model with zero-order infusion. The mean acyclovir concentrations at all time points after 1.0 h from the end of acyclovir infusion following probenecid administration were statistically higher than the corresponding mean acyclovir concentrations following the acyclovir infusion without probenecid administration. In the absence of probenecid, the renal clearance (248 ± 80 ml/min per 1.73 m2) accounted for 83% of the total clearance (300 ± 69 ml/min per 1.73 m2) and was almost threefold greater than the estimated creatinine clearance (90 ± 48 ml/min per 1.73 m2). After probenecid administration, there was a 32% decline in renal clearance (248 to 168 ml/min per 1.73 m2; p _ 0.05), a 40% increase in the area under the curve (91.3 to 127.6 nmol.h/ml; P < 0.05), and an 18% increase in the terminal plasma half-life (2.3 to 2.7 h; P < 0.01). Although statistically significant, these effects due to the influence of probenecid probably have only limited clinical importance. In this study we confirmed that acyclovir is eliminated predominantly by renal clearance, both by glomerular filtration and tubular secretion; our results suggested that at least part of the tubular secretion is inhibited by probenecid.Acyclovir, a potent anti-herpesvirus agent, is eliminated predominantly by renal excretion (2,4,5,7,13). The only significant metabolite of acyclovir which has been isolated to date is 9-carboxymethoxymethylguanine (4, 5), which accounts for less than 14% of the administered dose. The renal clearance of acyclovir after a single 1-h infusion is two-to threefold greater than the creatinine clearance (4,5,7,13). This suggests that acyclovir is eliminated by other renal mechanisms in addition to glomerular filtration and that renal tubular secretion may play an important role in acyclovir elimination. The mechanism of this tubular secretion is not known.Probenecid, an inhibitor of the organic acid transport system (1, 3), has been used frequently to elucidate the role of organic acid transport in the fate of various drugs (3). We conducted a study in human volunteers to evaluate the effects of probenecid on the pharmacokinetics and elimination of acyclovir. MATERIALS and METHODSPatient selection. Three patients (two females and one male) with a mean age of 47.3 years (range, 24 to 67 years) were selected. Each of these patients had a malignancy; two had a hematological malignancy, and one had carcinoma of the breast. The mean weight, height, and body surface area of these patients were 79.1 kg (range, 68 to 100 kg), 159 cm (range, 155.1 to 164 cm), and 1.89 m2 (range, 1.75 to 2.17), respectively. The prognosis for each patient was such that the life expectancy was at least 6 months, and in each case the lon...

Probenecid Improves Cardiac Function in Patients With Heart Failure With Reduced Ejection Fraction In Vivo and Cardiomyocyte Calcium Sensitivity In Vitro

“…Since that time, probenecid has been safely used as adjuvant therapy for other antibiotics,35 antivirals,22 and early antidepressants,36 as well as for the prevention of gout 14. The use of probenecid in patients has decreased in recent years as other therapeutic options for gout have emerged, though it is still actively used in basic science laboratories as a Fura‐2 blocker 37…”

A pharmacokinetic interaction study of didanosine coadministered with trimethoprim and/or sulphamethoxazole in HIV seropositive asymptomatic male patients

“…Although the occurrence of specific active transport systems has been confirmed for anions and cations [ 36,371, an overlap in the functions of these two transport systems has been illustrated. Probenecid, a classical inhibitor of anion active transport in the renal tubule, has been shown to inhibit renal excretion of 17-ketosteroid [ 381 (a neutral compound), acyclovir [39] (a nucleoside), and cimetidine [40] (a basic compound). More recently, the renal clearance of zidovudine, another nucleoside analogue, has been shown to decrease significantly when coadministered with either probenecid [41] (involvement of either anionic or nonspecific transport) or trimethoprim [ 331 (involvement of cationic transport).…”

Multiple Interactions of Cimetidine and Probenecid with Valaciclovir and Its Metabolite Acyclovir

“…Valaciclovir and acyclovir, which have anionic and cationic forms in plasma, are secreted by organic anion and cation transporters. Acyclovir CL R is reduced by probenecid (6), which was thought to be due to inhibition of the renal tubular secretion of acyclovir by the anionic pathway.…”

“…Valaciclovir and acyclovir, which have anionic and cationic forms in plasma, are secreted by organic anion and cation transporters. Acyclovir CL R is reduced by probenecid (6), which was thought to be due to inhibition of the renal tubular secretion of acyclovir by the anionic pathway.We investigated the effects of probenecid and cimetidine on valaciclovir pharmacokinetics, as these drugs have been reported to inhibit the metabolism of some compounds and the active membrane transport of a number of organic anions and cations (4,6,8,9,12). Additionally, we examined the effects of probenecid and cimetidine on the pharmacokinetics of acyclovir.…”

“…We investigated the effects of probenecid and cimetidine on valaciclovir pharmacokinetics, as these drugs have been reported to inhibit the metabolism of some compounds and the active membrane transport of a number of organic anions and cations (4,6,8,9,12). Additionally, we examined the effects of probenecid and cimetidine on the pharmacokinetics of acyclovir.…”