Preclinical toxicology studies with acyclovir: Acute and subchronic tests

Tucker, Walter E.; Macklin, A. W.; Szot, R.J.; Johnston, R.E.; Elion, Gertrude B.; Miranda, Paulo de; Szczech, George M.

doi:10.1016/s0272-0590(83)80107-9

Cited by 55 publications

(13 citation statements)

References 11 publications

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“…Simulation of Tubular Concentration for Acyclovir and Sulfamethoxazole. Acyclovir and sulfamethoxazole are associated with the precipitation of crystals in the distal tubular lumen, including collecting ducts in patients and nonhuman animals (Brigden et al, 1982;Tucker, 1982;Tucker et al, 1983;Sawyer et al, 1988;Perazella, 1999). To evaluate the relationship between tubular concentration and solubility, tubular concentrations of acyclovir and sulfamethoxazole were simulated using the population representative (a 20-yearold man; body weight, 81 kg) in a healthy volunteer population.…”

Section: Downloaded Frommentioning

confidence: 99%

Towards Further Verification of Physiologically-Based Kidney Models: Predictability of the Effects of Urine-Flow and Urine-pH on Renal Clearance

Matsuzaki¹,

Scotcher²,

Darwich³

et al. 2018

J Pharmacol Exp Ther

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In vitro-in vivo extrapolation (IVIVE) of renal excretory clearance (CL R ) using the physiologically based kidney models can provide mechanistic insight into the interplay of multiple processes occurring in the renal tubule; however, the ability of these models to capture quantitatively the impact of perturbed conditions (e.g., urine flow, urine pH changes) on CL R has not been fully evaluated. In this work, we aimed to assess the predictability of the effect of urine flow and urine pH on CL R and tubular drug concentrations (selected examples). Passive diffusion clearance across the nephron tubule membrane was scaled from in vitro human epithelial cell line Caco-2 permeability data by nephron tubular surface area to predict the fraction reabsorbed and the CL R of caffeine, chloramphenicol, creatinine, dextroamphetamine, nicotine, sulfamethoxazole, and theophylline. CL R values predicted using mechanistic kidney model at a urinary pH of 6.2 and 7.4 resulted in prediction bias of 2.87-and 3.62-fold, respectively. Model simulations captured urine flow-dependent CL R , albeit with minor underprediction of the observed magnitude of change. The relationship between drug solubility, urine flow, and urine pH, illustrated in simulated intratubular concentrations of acyclovir and sulfamethoxazole, agreed with clinical data on tubular precipitation and crystal-induced acute kidney injury. This study represents the first systematic evaluation of the ability of the mechanistic kidney model to capture the impact of urine flow and urine pH on CL R and drug tubular concentrations with the aim of facilitating refinement of IVIVE-based mechanistic prediction of renal excretion.

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Section: Downloaded Frommentioning

confidence: 99%

Towards Further Verification of Physiologically-Based Kidney Models: Predictability of the Effects of Urine-Flow and Urine-pH on Renal Clearance

Matsuzaki¹,

Scotcher²,

Darwich³

et al. 2018

J Pharmacol Exp Ther

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“…These crystals caused a dose-related obstructive nephropathy characterized by tubular blockage and dilatation and impairment of renal function. 9,29 The perfusate AM 188 concentrations at which saturation of renal excretion was observed in the current IPK studies (above 25 g/mL) are substantially greater than the concentrations required for in vitro anti-HBV effects (EC50 0.0383 g/mL; EC90 0.455 g/mL). 5 Although the plasma concentrations required to elicit an antiviral effect in humans remain to be determined, based on the relative concentrations for in vitro activity and saturation of renal handling as observed in the IPK, precipitation within the kidney is not anticipated to be an obstacle for the clinical use of AM 188 as an antiviral drug.…”

Section: Discussionmentioning

confidence: 76%

Renal excretion mechanisms of the antiviral nucleoside analogue AM 188 IN the rat isolated perfused kidney

Wang

Nation

Evans

et al. 2004

Clin Exp Pharmacol Physiol

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1. AM 188 is an antiviral guanosine analogue that undergoes extensive renal excretion in humans. The present study was designed to investigate the disposition of AM 188 over a range of concentrations in the rat isolated perfused kidney (IPK) to explore the mechanisms involved in its renal handling. 2. Right kidneys of male Sprague-Dawley rats (n = 23) were isolated and perfused in recirculating mode with Krebs'-Henseleit (pH 7.4) buffer containing 0.65% bovine serum albumin, 3.6% dextran, amino acids and glucose. [14C]-Inulin was added to the perfusate reservoir to permit estimation of glomerular filtration rate (GFR). [3H]-AM 188 and unlabelled AM 188 were added to the perfusate as a bolus initially, followed by a constant rate of infusion at 5, 25, 125, 500 or 1000 microg/min to achieve initial target perfusate concentrations of 1, 5, 25, 100 or 200 microg/mL, respectively. During the 130 min over which AM 188 was infused, urine was collected in 10 min intervals (commencing 10 min after the bolus dose) and perfusate was collected at the mid-point of these intervals to permit calculation of the renal clearance (CLR) of AM 188. Binding of AM 188 in perfusate, measured using ultrafiltration, was negligible. 3. The bolus dose and infusion regimen produced relatively stable AM 188 concentrations in perfusate in the 5, 25 and 125 micro g/min groups and progressively increasing concentrations in the 500 and 1000 microg/min groups. High-pressure liquid chromatography analysis of IPK perfusate and urine suggested that there was no or negligible metabolism of AM 188 in the kidney. The CLR/GFR ratio for AM 188 (mean+/-SD) was 5.76 +/- 1.57, 5.99 +/- 0.52, 6.02 +/- 1.47, 3.38 +/- 0.26 and 1.08 +/- 0.42 in the 5, 25, 125, 500 and 1000 microg/min groups, respectively, showing significant reductions at the two highest infusion rates (P < 0.05). Although there was no difference between the five groups in the distribution of AM 188 between kidney tissue and perfusate (KT/P), at the end of perfusion the corresponding urine-to-tissue concentration ratio declined significantly in the 1000 microg/min group. 4. AM 188 undergoes substantial net renal secretion over a wide range of perfusate concentrations. A reduction in renal clearance at perfusate concentrations above 25 microg/mL could be due to saturation of carrier-mediated transport at the brush border membrane and/or a solubility limitation leading to precipitation of AM 188 in tubular cells and/or tubular urine.

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“…Systemic administration of drugs with radiomimetic or antimitotic activity can cause hypoplastic changes (atrophy or hypoplasia) in the esophageal mucosa in addition to the well-known pathological changes in the gastric and intestinal mucosa. 176…”

Section: Drug-induced Changes In Toxicity Studiesmentioning

confidence: 99%

“…363,409,410 Antiviral drugs may also show radiomimetic effects on the gastrointestinal mucosa such as seen in dogs treated with high doses of acyclovir. 176 There are also reports of experimental drugs of other therapeutic classes also producing intestinal damage as a result of their generalized antimitotic effects. 550 The small intestine is very radiosensitive and changes are seen in patients after ionizing radiation therapy.…”

Section: Drug-induced Inflammation and Ulcerationmentioning

confidence: 99%

“…231,545 In studies with the antiviral agent acyclovir, a radiomimetic effect was noted in the gastrointestinal tract of dogs at high doses but not rodents. 176 Another example is the villous atrophy described in rats following treatment with an experimental antibacterial agent ICI 17,363, which was believed to arise as a result of both interference with cell division and a direct effect on the surface epithelial cells. 563 The effects of ICI 17,363 were characterized by atrophy of villi with dilatation of crypts and atypical features in the crypt epithelium suggestive of an effect on mitotic activity.…”

Section: Villous Atrophy Hypoplasiamentioning

confidence: 99%

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