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Biomedical subjects

R E Galinsky

Publications and source records attributed to R E Galinsky.

At least 37 records · Page 2Linked to original sources
PubMed1989

Perinatal cimetidine exposure has no apparent effect on hepatic drug oxidative or conjugative activity in adult male rat offspring.

UNLABELLED: Perinatal exposure of male rat pups to cimetidine has been reported to 'feminize' gonadal and sexual function and to reduce serum testosterone in adult male offspring. This study examined whether perinatal cimetidine exposure altered the androgen 'imprinting' of sex differences in mature male hepatic biotransformation capacities. During the perinatal period, dams were infused with cimetidine (18 mg/kg/day) through Alzet osmotic pumps placed subcutaneously beginning at 10 days of gestation. Pump function was confirmed by weekly high-performance liquid chromatographic analysis of maternal urine for unchanged cimetidine. Male pups were culled at birth with continued exposure to cimetidine in breast milk until weaning. At about 100 days of age, in vitro and in vivo drug oxidative and conjugative activities were measured in mature males. Early cimetidine exposure did not alter hepatic oxidative (cytochrome P-450 content or monooxygenase activity) or conjugative (UDP-glucuronosyltransferase activity towards testosterone, morphine, 1-naphthol, estrone, or sulfotransferase activity towards acetaminophen or glycolithocholate) capacities in mature males. Two sulfotransferase isoenzyme activities (acetaminophen sulfotransferase 2 and bile salt sulfotransferase I) previously shown to be regulated by gonadal hormones were also unchanged. Serum testosterone was unaffected by perinatal cimetidine exposure. Moreover, there were no effects of perinatal cimetidine exposure on in vivo pharmacokinetics or metabolic fate of acetaminophen. CONCLUSION: Perinatal exposure of male pups to doses of cimetidine similar to those used in humans did not appear to affect the imprinting of sex differences on in vitro hepatic drug metabolism or elimination kinetics of acetaminophen.

Acetaminophen↗
PubMed1988

Effect of taurolithocholate on in vivo sulfation and glucuronidation of acetaminophen in rats.

Taurolithocholate produces a prompt, complete, and reversible cessation of bile flow in rats. This is associated with impaired hepatic oxidative drug-metabolizing activity. The purpose of this study was to examine the effects of taurolithocholate-induced cholestasis on in vivo conjugation. The pharmacokinetics of acetaminophen and the two major processes specifically responsible for its elimination, namely, the formations of acetaminophen sulfate and acetaminophen glucuronide, were used to assess hepatic conjugating activity. A 30-mg/kg bolus of acetaminophen was administered intravenously to rats 2 hr (acute cholestasis) or 20 hr (postcholestasis) after intravenous pretreatment with sodium taurolithocholate, 5 mumol/100 g body weight. Acute cholestasis increased the total clearance of acetaminophen 20%, the partial clearance to acetaminophen sulfate 12%, and the partial clearance to acetaminophen glucuronide 85%. Postcholestasis, these parameters had significantly decreased compared to those during acute cholestasis and were comparable to control values. The results show that cholestasis does not impair acetaminophen conjugation in the rat.

Acetaminophen↗
PubMed1987

Pharmacokinetic consequences and toxicologic implications of metyrapone-induced alterations of acetaminophen elimination in man.

This study examined the effect of metyrapone on the elimination rate of acetaminophen and on the apparent formation rate of acetaminophen metabolites in man. Metyrapone treatment, 1.5 g, increased the half-life of acetaminophen, decreased the fraction of the dose recovered in the urine as the glucuronide and increased the fraction of the dose recovered in urine as the sulfate and mercapturate conjugates. The apparent rate constant for the formation of acetaminophen glucuronide was significantly decreased by metyrapone while the apparent rate constants for the formation of the sulfate and mercapturic acid metabolites were unchanged or slightly increased, respectively. These data indicate that metyrapone inhibits acetaminophen glucuronidation and possibly enhances the oxidation of acetaminophen to its quantitatively minor yet highly toxic reactive metabolite. The extent to which the parallel pathways of acetaminophen elimination are also affected by inhibitors of cytochrome P-450-mediated oxidation will limit the efficacy of these types of potential antidotes for the treatment of acetaminophen overdose.

Acetaminophen↗
PubMed1987

Effect of chronically administered ketoconazole on the elimination of theophylline in man.

Ketoconazole, a nitrogen-substituted imidazole, has been shown to be a potent in vitro inhibitor of cytochrome P-450-mediated metabolic processes. Conflicting reports exist concerning the in vivo effect of ketoconazole on concomitantly administered drugs that require these metabolic processes for clearance. Therefore, the effect of multiple-dose ketoconazole on the elimination of theophylline, a drug metabolized by cytochrome P-450, in ten healthy, nonsmoking males (aged 18-40 years) was evaluated. Each subject received aminophylline 6 mg/kg iv before and at the end of seven days of ketoconazole 200 mg/d po. Theophylline serum concentrations were determined by fluorescence polarization immunoassay (TDx) at 12 time points over the 24-hour period following each infusion. No statistical difference (two-tailed t-test) in half-life (mean +/- SD 7.8 +/- 1.8 vs. 8.2 +/- 1.9 h) or clearance (0.797 +/- 0.201 vs. 0.722 +/- 0.133 ml/min/kg) could be demonstrated for theophylline before or after ketoconazole administration. Theophylline dosage adjustment is probably not necessary for concomitant theophylline and ketoconazole drug therapy.

Adolescent↗
PubMed1987

Acetaminophen sulfation deficit in obese rats overfed an energy-dense cafeteria diet.

The current studies examine acetaminophen pharmacokinetics and biotransformation in obese animals for possible shifts in metabolic conjugation reactions. Obesity was produced in Sprague-Dawley rats with an energy-dense cafeteria feeding regimen. Acetaminophen half-life remained unchanged and apparent volume of distribution increased slightly in obese versus pellet-fed control rats following an ip dose of 287 mg/kg. However, obese animals exhibited lower plasma concentrations of acetaminophen sulfate and excreted less sulfate conjugate but more glucuronide conjugate in urine. Absolute clearance of acetaminophen from plasma was similar for both groups of rats but formation clearance of acetaminophen sulfate was lower and formation clearance of acetaminophen glucuronide and was higher than control in obese rats. Renal clearance of unchanged drug and both conjugated metabolites appeared to rise with the degree of obesity. The many parallels in acetaminophen disposition shared with the obese human show the overfed rat to be a promising model for metabolic and physiologic changes associated with human obesity.

Acetaminophen↗
PubMed1987

Unexpected accumulation of acyclovir in breast milk with estimation of infant exposure.

Although acyclovir is prescribed to women of reproductive age, no information currently exists regarding the advisability of its use in lactating women. This report documents the first known case of acyclovir transfer to an infant through breast milk. Maternal plasma, milk, and infant urine were collected following a 200-mg oral dose of acyclovir. The drug concentration in breast milk exceeded the corresponding plasma concentration except at the time of peak plasma concentration. This would not be expected on the basis of simple diffusion, and might be caused by a facilitated or active transport mechanism. Such a mechanism has not been described for any drug in human breast milk. Subtherapeutic amounts of acyclovir were documented in the infant, and we discuss the potential effects on neonatal immune function. The use of acyclovir in lactating women remains controversial until further study can clarify pertinent questions.

Acyclovir↗
PubMed1986

Dissociation of increased sulfation from sulfate replenishment and hepatoprotection in acetaminophen-poisoned mice by N-acetylcysteine stereoisomers.

N-Acetylcysteine stereoisomers were compared for their ability to alter the sulfation and hepatotoxicity of acetaminophen. The clinically used L-isomer increased urinary excretion of inorganic sulfate 2-3 fold and prevented liver injury, but failed to increase acetaminophen sulfation in mice. Conversely, the nonphysiologic D-isomer failed to increase urinary excretion of inorganic sulfate or prevent hepatotoxicity, but increased acetaminophen sulfation appreciably (by 39%). The basis of the incongruence between changes in the availability of inorganic sulfate and the sulfation of acetaminophen is not known. These data indicate that a modest increase in acetaminophen sulfation, occurring alone following N-acetylcysteine treatment, is insufficient to explain the profound efficacy of the antidote in mice, and further suggest that this holds true for other species, such as humans, that are comparatively poor in the sulfoconjugation of acetaminophen.

Acetaminophen↗
PubMed1986

Influence of advanced age on the formation and elimination of acetaminophen metabolites by male rats.

The effects of aging on acetaminophen metabolism and elimination in male Fischer 344 rats were examined after intravenous injection of 300 mg/kg. Age as a variable had only a small effect on the total clearance of acetaminophen. However, the fraction of administered dose recovered from urine as acetaminophen sulfate and the partial clearance to acetaminophen sulfate decreased while the fraction recovered as acetaminophen glucuronide and the partial clearance to acetaminophen glucuronide increased with increasing age. Renal clearances of acetaminophen and acetaminophen glucuronide were unchanged while that of acetaminophen sulfate decreased. These data point to an age-related decrease in sulfation and increase in glucuronidation of acetaminophen and further emphasize that the major conjugated metabolites are excreted by renal transport processes that operate under separate control. Moreover, they raise the possibility that advancing age may be accompanied by a general decline in processes that govern sulfate conjugate formation and elimination.

Acetaminophen↗
PubMed1986

Effect of aging on drug-metabolizing enzymes important in acetaminophen elimination.

The effects of aging on selected drug-metabolizing enzyme activities, the pattern of phenol and bile salt sulfotransferase isoenzymes and the pharmacokinetics of acetaminophen were examined in male Fischer 344 rats at ages 5, 14 and 25 months. Aging decreased sulfotransferase activity toward acetaminophen while activity toward glycolithocholate increased with age. Glucuronosyltransferase activity toward estrone increased with age, while activity toward testosterone, morphine and naphthol remained constant. Glutathione-S-transferase (1-chloro-2,4-dinitrobenzene) activity was also unchanged through the various age groups. Cytochrome P-450 content and monooxygenase activity (p-nitroanisole demethylation) activity decreased with advancing age. Overall, the age-related in vitro changes in enzyme activities approached or equaled values measured in 5-month-old female Fischer 344 rats. Moreover, age-related alterations in total phenol sulfotransferase activity and the isozyme pattern paralleled changes in the in vivo elimination kinetics and metabolic fate of acetaminophen. The fraction of drug excreted as the sulfate conjugate and the partial clearance to acetaminophen sulfate decreased with increasing age. Conversely, the fraction excreted as the glucuronide and the partial clearance to acetaminophen glucuronide increased with increasing age. There was no effect of aging on the total clearance of acetaminophen. The gender-related differences in the pattern of sulfotransferase isozyme activity toward phenolic and bile salt acceptors disappeared with age. Age-related changes in sulfation and perhaps glucuronidation in male rats appear to feminize hepatic biotransformation and may arise due to altered gonadal hormone status.

Acetaminophen↗
PubMed1986

Role of glutathione turnover in drug sulfation: differential effects of diethylmaleate and buthionine sulfoximine on the pharmacokinetics of acetaminophen in the rat.

The purpose of this investigation was to examine the role of altered glutathione turnover in regulating sulfation. After diethylmaleate (3.9 mmol/kg i.p.) or buthionine sulfoximine (6 mmol/kg i.p.) injection, rats received an i.v. dose (30 or 150 mg/kg) of acetaminophen. Diethylmaleate pretreatment decreased the total clearance and increased the half-life of acetaminophen. The fraction of the dose recovered in the urine as acetaminophen sulfate and the partial metabolic clearance to acetaminophen sulfate were substantially diminished by diethylmaleate. Conversely, buthionine sulfoximine pretreatment increased the total clearance of acetaminophen and increased the partial metabolic clearance to acetaminophen sulfate. Diethylmaleate produces a prompt increase in glutathione turnover. This more rapidly uses available cysteine, the rate-limiting precursor of glutathione (and probably inorganic sulfate), thus limiting the availability of inorganic sulfate for sulfate conjugation. Importantly, diethylmaleate decreased the total clearance of acetaminophen and the partial clearance to acetaminophen sulfate at a dose of acetaminophen that does not produce complete sulfate depletion. This indicates that diethylmaleate may inhibit sulfation by mechanisms in addition to limiting sulfate availability. Buthionine sulfoximine selectively inhibits gamma-glutamylcysteine synthetase, thereby preventing cysteine utilization for glutathione resynthesis. Cysteine presumably becomes more available for oxidation to inorganic sulfate. These data suggest that glutathione is not normally converted to cysteine for further oxidation to sulfate when the latter endogenous ion is depleted.

Acetaminophen↗
PubMed1984

Absorption and metabolism of acetaminophen shortly before parturition.

The absorption and metabolism of acetaminophen 1 g po (as tablets) by a healthy 27-year-old woman was determined one day before parturition and again 38 days after parturition. Based on the urinary excretion data, acetaminophen was absorbed much more slowly and incompletely, and the metabolic conversion of acetaminophen to the sulfate conjugate was less pronounced on the last day of pregnancy than 38 days after parturition. These results are consistent with reports of decreased gastric emptying rate in late human pregnancy and with decreased acetaminophen sulfation by rats during the last days of gestation.

Acetaminophen↗
PubMed1984

Evaluation of activated charcoal-sodium sulfate combination for inhibition of acetaminophen absorption and repletion of inorganic sulfate.

Activated charcoal is an effective inhibitor of acetaminophen absorption while sodium sulfate can prevent the depletion of endogenous inorganic sulfate associated with the formation of acetaminophen sulfate. Administration of activated charcoal plus sodium sulfate soon after acetaminophen overdose may reduce acetaminophen absorption and facilitate the elimination of absorbed acetaminophen by providing sufficient sulfate ion for rapid sulfation of the drug. This investigation was designed to determine if sodium sulfate modifies the inhibitory effect of activated charcoal on acetaminophen absorption or if activated charcoal affects the absorption of sodium sulfate. Eight normal adults received, on separate occasions, 1 g acetaminophen, 1 g acetaminophen and 18 g sodium sulfate (decahydrate), 1 g acetaminophen with 10 g activated charcoal and 1 g acetaminophen, with 10 g activated charcoal and 18 g sodium sulfate, in random order. Urine was collected for 48 hours and assayed for acetaminophen and its major metabolites and for inorganic sulfate. The results confirm that activated charcoal can reduce acetaminophen absorption and show that oral administration of activated charcoal with sodium sulfate does not alter the inhibitory effect of activated charcoal on acetaminophen absorption or the bioavailability of the sulfate. A combination of activated charcoal and sodium sulfate may therefore be useful for the initial management of acetaminophen overdose.

Absorption↗
PubMed1982

Massive intoxication with acetaminophen and propoxyphene: unexpected survival and unusual pharmacokinetics of acetaminophen.

A 28-year-old woman ingested an estimated 58 g acetaminophen and 9 g propoxyphene 20 h before hospitalization. Her serum acetaminophen concentration at 22 h was 485 micrograms/mL and declined with an unusually long half-life of 14 h. Hemodialysis for 4 h (started at 36 h) reduced the acetaminophen concentration from 250 to 32 micrograms/mL. The patient's complete recovery was remarkable because of the large amounts of drugs ingested, the delayed treatment, and prior exposure to enzyme inducers (known to increase acetaminophen hepatotoxicity). Administration of N-acetylcysteine prevented inorganic sulfate depletion usually caused by acetaminophen and may have increased the formation of acetaminophen sulfate. Some patients eliminate large overdoses of acetaminophen very slowly. Measures to enhance the elimination of this drug and its toxic metabolite by these individuals may be useful even when diagnosis or hospitalization is delayed.

Acetaminophen↗