Acyclovir kinetics after intravenous infusion

107

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...

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confidence: 99%

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confidence: 99%

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

Laskin¹,

Miranda²,

King³

et al. 1982

107

“…This antiherpetic agent has demonstrated low toxicity, good metabolic stability, and broad tissue distribution in preclinical trials (9,24). Therefore, acyclovir can be considered an antiviral agent with great therapeutic potential in humans.…”

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confidence: 99%

In vitro susceptibility of varicella-zoster virus to acyclovir

Biron¹,

Elion²

1980

210

The in vitro susceptibility of five strains of varicella-zoster virus to acyclovir was examined by the plaque-reduction method in human diploid lung cells. The 50% effective doses of acyclovir ranged from 2.06 ,LM to 6.28 ,uM in a 7-day assay, with a mean of 3.65 tiM. Irreversible inhibition of plaque formtation was achieved by drug doses exceeding the 50% effective dose for plaque reduction but nontoxic to the cells. Studies on the relative in vitro susceptibility of varicella-zoster virus and herpes simplex virus types 1 and 2 to acyclovir suggested that varicella-zoster virus is two-to eightfold less susceptible to the drug. The antiviral potency of acyclovir for varicella-zoster virus in vitro was compared with that of several other nucleoside analogs. Analysis of the metabolism of acyclovir in varicellazoster virus-infected WI-38 cells revealed that, as with herpes simplex virus types 1 and 2, the formation of the triphosphate forms of the drug is specific to viral infection.

“…Among 23 human patients who were treated with ACV intravenously at a dose of 5 mg/kg three times a day for 5 days, the only toxicity observed was a reversible increase in blood urea nitrogen in 2 (28). In another study (9) there was no indication of toxicity either clinically or from laboratory observations in any of the human subjects after a 1-h intravenous infusion of ACV at doses of up to 5 mg/kg. In our study, no gross or microscopic lesions were observed that could be attributed to drug toxicity after we had given newborn rabbits 6 or 12 daily intraperitoneal injections of the drug that amounted to 50 mg/kg of body weight per day.…”

Section: Methodsmentioning

confidence: 91%

“…Toxicity, rapid metabolic breakdown, or insolubility of these compounds further limited their therapeutic use. Acyclovir (ACV) [9-(2-hydroxyethoxymethyl)-guanine], formerly known as "acycloguanosine," is an attractive candidate for treatment of neonatal HSV infections, since it has a high level of activity against HSV infections both in vitro (10) and in vivo (17,28) with minimal toxicity in vivo (9,28,29). This paper reports the results on a study on the efficacy of ACV against HSV type 2 (HSV-2) skin infections in newborn rabbits, an experimental model described previously (20).…”

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confidence: 99%

Acyclovir therapy of neonatal herpes simplex virus type 2 infections in rabbits

Sicher¹,

Oh²

1981

New Zealand white rabbits less than 30 h old were inoculated subcutaneously with 103 50% tissue culture infectious doses of type 2 herpes simplex virus. The animals were randomly assigned to a treatment schedule of daily intraperitoneal injections of acyclovir, beginning on the day of virus inoculation for 6 or 12 days, on post-inoculation day 1 for 6 days, or on post-inoculation day 2 for 6 days. The acyclovir was given in doses of 50 mg/kg of body weight per day. Similarly infected animals receiving daily intraperitoneal injection of Eagle minimum essential medium served as controls. All of the control animals died on day 4 or 5 after inoculation. At death they exhibited severe skin lesions, viremia, and dissemination of virus in various visceral organs and spinal as well as trigeminal ganglia. In contrast, animals treated with acyclovir failed to develop significant skin lesions, and death did not occur while treatment continued. Termination of treatment after 6 days resulted in late-onset fatal disease and virus isolation from the brain in many rabbits regardless of the treatment schedule. No such late fatality was observed and no virus could be detected from the brain when treatment was initiated on the day of virus inoculation and continued for 12 consecutive days. With respect to all of the variables studied, treatment for 12 days beginning on the day of virus inoculation was most effective.In the past, iododeoxyuridine (4,15,16,19,23,26,31), cytosine arabinoside (6,27), and adenine arabinoside (5, 32) have been used in the treatment of herpes simplex virus (HSV) infections in newborns with varied results. Toxicity, rapid metabolic breakdown, or insolubility of these compounds further limited their therapeutic use. Acyclovir (ACV) [9-(2-hydroxyethoxymethyl)-guanine], formerly known as "acycloguanosine," is an attractive candidate for treatment of neonatal HSV infections, since it has a high level of activity against HSV infections both in vitro (10) and in vivo (17, 28) with minimal toxicity in vivo (9,28,29). This paper reports the results on a study on the efficacy of ACV against HSV type 2 (HSV-2) skin infections in newborn rabbits, an experimental model described previously (20). MATERIALS AND METHODSNewborn rabbits. New Zealand white rabbits 24 to 30 h old were used as in our previous study (20 by dissolving 225 mg of ACV in 10 ml of 0.1 N NaOH, sterilizing by filtration through a membrane filter (Millipore Corp., Bedford, Mass.), and adjusting to pH 8.0 with 0.1 N HCI. The sterile stock ACV solution was stored at 4°C and further diluted in minimal essential medium to obtain the concentration of 5 mg/ ml as needed.Collection of blood and tissue specimens for virus assay and histopathology. Immediately after sacrifice, 2 ml of cardiac blood was obtained, heparinized, and processed for virus isolation. Duplicate specimens of heart, lungs, thymus, liver, spleen, kidneys, brain, and both adrenal glands and eyes were removed. One specimen or organ was fixed in Bouin solution for histological study, and th...