Harvey C. Krasny

Effect of renal failure on the pharmacokinetics of acyclovir

Abstract To determine the effect of renal failure on the pharmacokinetics of acyclovir in patients with end-stage renal disease (ESRD), we studied six anuric subjects on chronic hemodialysis. Each subject received a single one-hour intravenous infusion of acyclovir (2.5 mg/kg). We compared these anuric subjects with 13 subjects with normal renal function (NRF) who had received a single dose of acyclovir (2.5 to 15 mg/kg) in an identical fashion. The kinetics were well-described by a two-compartment open model. The mean terminal plasma half-life of acyclovir in subjects with ESRD was 19.5 ± 5.9 hours (mean ± SD) compared with 2.9 ± 0.8 hours in our subjects with NRF. In subjects with renal failure the mean (± SD) peak, eight- and 24-hour plasma acyclovir concentrations were 37.5 ± 23.3, 10.3 ± 2.9, and 6.4 ± 2.4, μ M respectively. Forty-eight hours after the start of acyclovir infusion, the subjects were hemodialyzed for six hours. The pre- and post-hemodialysis acyclovir plasma levels were 2.74 ± 1.38 and 1.11 ± 0.60 μ M , respectively. The total body clearance of acyclovir (28.6 ± 9.5 ml/min/1.73 m 2 ) in ESRD was found to be approximately 10 percent of that previously seen in subjects with normal renal function (307 ± 98.4 mg/min/1.73 m 2 ). The volume of distribution at steady state was significantly less in the subjects with ESRD than in subjects with NRF. Acyclovir was readily hemodialyzable with an extraction coefficient of 0.45 ± 0.12 and a fourfold enhancement in the elimination of acyclovir during dialysis. Suggestions for acyclovir dosage modifications for patients with ESRD are provided.

Formation of nucleotides of [6-14C]allopurinol and [6-14C]oxipurinol in rat tissues and effects on uridine nucleotide pools

Abstract Allopurinol-1-ribonucleotide, oxipurinol-1-ribonucleotide and oxipurinol-7 ribonucleotide have been found in concentrations ranging from less than 10−9-10−6M in rat liver and kidney after administration of [6-14C]allopurinol. The amounts and relative proportions of each nucleotide were dependent upon the dose, route of administration and time. Red cells contained about one-tenth the amount of allopurinol-1-ribonucleotide present in liver and no oxipurinol ribonucleotides were detectable. Brain contained no analog nucleotides. Both of the oxipurinol ribonucleotides were recovered after administration of [6-14Cloxipurinol. In general, the biological half-lives of the nucleotides were related to the amount of the free bases present in the tissues. There was no evidence for the presence of ribonucleoside di- or triphosphates of allopurinol or oxipurinol. Allopurinol and oxipurinol ribonucleotides have been reported to be inhibitors of orotidylate decarboxylase in vitro. High doses of allopurinol and oxipurinol caused a transient decrease of UMP and UDP pools in rat liver, which returned to control levels after 3 hr, whereas UTP levels were actually elevated. In kidney, allopurinol caused no changes in UMP, UDP or UTP levels at any of the times examined, even after a 100 mg/kg, i.p., dose. These findings suggest that control mechanisms can maintain uridine nucleotide levels in a normal range, even in the presence of strong inhibitors of de novo UMP biosynthesis.

Species differences in the disposition of acyclovir

The disposition of acyclovir was investigated in several species. The drug was well distributed into all the tissues, including the brain, in mice and rats. Binding of acyclovir to plasma proteins was 36 percent or lower. After intravenous bolus dosing (20 mg/kg) in dogs, the plasma acyclovir concentration-time profile, determined by radioimmunoassay, showed a biphasic decline with a half-life in the elimination phase of 2.3 +/- 0.1 hours. The volume of distribution (Vd beta) of 1.2 +/- 0.2 liters/kg indicated distribution of drug into the tissues. Marked species differences were observed in the gastrointestinal absorption and biotransformation of acyclovir. Oral dosing produced better absorption in dogs and mice than in rats and rhesus monkeys. More than 95 percent of the radioactivity in the urine derived from a 14C-acyclovir parenteral dose was recovered as the unchanged drug in mice, rats, and dogs. Minor urinary metabolites were characterized by high-performance liquid chromatography as 9-carboxymethoxymethylguanine (CMMG) and 8-hydroxy-9-(2-hydroxyethoxymethyl)guanine. In other species--guinea pig, rabbit, and rhesus monkey--up to 40 percent of the radioactivity in the urine consisted of these metabolites.

Influence of hemodialysis on acyclovir pharmacokinetics in patients with chronic renal failure

The pharmacokinetic disposition of acyclovir was studied in six patients with chronic renal failure (CRF) and anuria. At the end of a one-hour intravenous infusion (2.5 mg/kg), the mean peak acyclovir plasma level (+/- SD), determined by radioimmunoassay, was 37.5 +/- 24.2 microM (8.4 +/- 5.4 microgram/ml), twice the level found at this dose in patients with normal renal function (NRF). In the CRF volunteers, significant plasma levels (3.0 +/- 1.4 microM) persisted at 47 hours after drug administration (before hemodialysis) whereas in the NRF patients levels dropped to less than 1 microM by 11 hours. Hemodialysis was started 47 hours after infusion and was continued for six hours. The pre-dialysis plasma drug level was reduced by 61.5 percent at 0.25 to 1.5 hours after the end of dialysis. The mean plasma t 1/2 during dialysis of 5.4 hours, the extraction ratio of 0.44, and the dialysis clearance for plasma of 113 ml/min indicate that acyclovir is efficiently removed by hemodialysis. One-half the suggested intravenous dose for a particular indication can be given every 24 hours and a similar replacement dose should be given after each dialysis.

Separation of 6-thiopurine derivatives on deae-sephadex columns and in the high-pressure liquid chromatograph

Conditions are described for the separation of 6-thiopurine derivatives of pharmacological interest, both on large columns of DEAE-Sephadex A-25 by a modified procedure of Caldwell and in the Varian Aerograph LCS-1000 high-pressure liquid chromatograph. It was found that the triethylammonium acetate buffer, pH 4.7, used by Caldwell caused extensive degradation of 6-thiopurines containing an unsubstituted thiol group, and that this decomposition could be prevented by the addition of 10 mM β-mercaptoethanol. Elution profiles are presented for a number of synthetic 6 thiopurine derivatives investigated by these two chromatographic procedures.

Metabolic fate of radioactive acyclovir in humans

The metabolic fate and the kinetics of elimination of [8-14C]acyclovir in plasma and blood was investigated in five cancer patients. Doses of 0.5 and 2.5 mg/kg were administered by one-hour intravenous infusion. Radioactivity was distributed nearly equally in blood and plasma. The plasma and blood concentration-time data were defined by a two-compartment open pharmacokinetic model. The overall mean acyclovir plasma half-life and total body clearance +/- SD were 2.1 +/- 0.5 hours and 297 +/- 53 ml/min/1.73 m2. Binding of acyclovir to plasma proteins was 15.4 +/- 4.4 percent. The radioactive dose was excreted predominantly in the urine (71 to 99 percent) with less than 2 percent excretion in the feces and only trace amounts of radioactivity in the expired air. Reverse-phase high-performance liquid chromatography indicated that 9-carboxymethoxymethylguanine was the only significant urinary metabolite of acyclovir accounting for 8.5 to 14.1 percent of the dose. A minor metabolite (less than 0.2 percent of dose) had the retention time of 8-hydroxy-9-(2-hydroxyethoxymethyl)guanine. Unchanged urinary acyclovir ranged from 62 to 91 percent of the dose. There was no indication of acyclovir cleavage to guanine. The renal clearances of acyclovir were three times higher than the corresponding creatinine clearances.

Preclinical toxicology studies with acyclovir: Carcinogenicity bioassays and chronic toxicity tests

Acyclovir (ACV), a nucleoside analog that is a new herpes-specific antiviral drug, was given by gavage at 50, 150 and 450 mg/kg/day to Sprague Dawley rats and Swiss mice for most of their lifetime to assess chronic toxicity and carcinogenicity. Treatment with ACV did not shorten the lifespan of either rats or mice. In fact, female mice given 150 and 450 mg/kg/day had significantly longer mean durations of survival than control female mice when analyzed by the life table technique. There were no signs of toxicosis produced by chronic exposure to ACV in either the rats or mice, and there was no drug-related increase in neoplasms in either species. Four groups of Beagle dogs were initially given daily oral doses of 15, 45 or 150 mg/kg ACV in a 1 year chronic toxicity study. Dogs treated at 150 mg/kg/day vomited, had diarrhea, consumed less feed and lost weight within 2 weeks. Dogs treated at 45 mg/kg/day also had minimal signs of gastrointestinal toxicosis. These dose levels were then decreased to 60 and 30 mg/kg/day for the rest of the one year test period. With the exception of occasional and inconsistent emesis and diarrhea, the 60 mg/kg/day dose level was well tolerated. Some mid and high dose dogs had sore paws due to erosion of footpads and cracking, splitting and loosening of the nails first becoming evident during the 13th week of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolism of Desciclovir, a Prodrug of Acyclovir, in Humans After Multiple Oral Dosing

Desciclovir (DCV), a prodrug of the antiherpetic agent acyclovir (ACV), is converted in humans to ACV, presumably by xanthine oxidase. Further metabolism of these two compounds was investigated in six human volunteers given 250 mg DCV orally every eight hours for ten days plus one dose on day 11. The mean percent dose recovered in urine (24 hr) on days 2, 5, and 10 as carboxy‐DCV (2%) and as carboxy‐ACV (14%) along with recoveries of DCV (6%) and ACV (62%) gave a mean total of 84% cleared over a 24‐hour period at steady state. Carboxyl metabolites were not found in the plasma of these same subjects at peak DCV concentration on dose day 11. The ratios of DCV and ACV to their corresponding carboxyl metabolites in urine were 4:1 and 3:1, respectively, suggesting that there is little or no difference in the efficiency of these two substrates for oxidation to their carboxylic acid metabolites.

Oxypurine and 6-Thiopurine Nucleoside Triphosphate Formation in Human Erythrocytes

A variety of oxypurines and 6-thiopurines could be transformed by intact erythrocytes to their nucleoside triphosphate forms when incubations were extended for up to 24 hrs. The specific nucleotide monophosphate kinases which accomplish these reactions in erythrocytes were not identified but their ability to utilize 6-thioIMP, 6-thioXMP and 6-methylthioGMP as substrates, albeit very slowly, is clearly implied by these results. S-methylation of 6-thiopurines was demonstrated in erythrocytes incubated with physiological amounts of methionine-(CH3-3H). 6-Methylthioguanosine triphosphate and 6-methylmercaptopurine riboside triphosphate were formed in micromolar amounts, probably from the corresponding thiopurine nucleotides by methyl transfer from S-adenosylmethionine.