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Biomedical subjects

R E Galinsky

Publications and source records attributed to R E Galinsky.

45 records · Page 3Linked to original sources
PubMed1979

Diazepam kinetics in acute alcohol withdrawal.

We performed a within-subject comparison of the kinetics of diazepam given to 7 alcoholic subjects during acute alcohol withdrawal and again after detoxification. The initial rapid exponential decline of plasma diazepam concentrations (t1/2 alpha) was more rapid during (0.21 +/- 0.03 hr) than after withdrawal (0.44 +/- 0.14 hr, p less than 0.05). Terminal t1/2, clearance, and volumes of distribution changed in individual patients, but mean values did not change. Protein binding was less in patients (93.4 +/- 2.4%) than in healthy controls (97.0 +/- 1.0, p less than 0.05). The effects of alcohol withdrawal on diazepam disposition do not explain the high doses of diazepam commonly required to treat the withdrawal.

Adult↗
PubMedDate not supplied

The depression of hepatic drug conjugation reactions in rats after lipid-free total parenteral nutrition administered via the portal vein.

BACKGROUND: Total parenteral nutrition provides nutrition support in patients who are unable to eat. Long-term parenteral nutrition is accompanied by alterations in gut and liver function including changes in drug metabolism. This study examined the effects of lipid-free total parenteral nutrition in rats on (1) the overall elimination pharmacokinetics of acetaminophen, (2) changes in sulfation and glucuronidation pathways during acetaminophen elimination, and (3) hepatic drug metabolizing enzyme activities determined in vitro. METHODS: Chronic indwelling catheters were implanted in the aorta, inferior vena cava, and portal vein of adult male Sprague-Dawley rats. Total parenteral nutrition, consisting of 25% dextrose, 5% amino acids, electrolytes, and vitamins, was infused via the portal vein for up to 14 days. Acetaminophen pharmacokinetics were characterized in vivo and selected drug metabolizing enzyme activities were determined in vitro. RESULTS: Parenteral nutrition for 10 days decreased the total clearance of acetaminophen by 23% (from 11.5 +/- 1.4 to 8.9 +/- 1.4 mL/min per kg; p < .05) and decreased the formation clearance to acetaminophen sulfate (from 6.2 +/- 0.4 to 3.9 +/- 0.5 mL/min per kg; p < .05). Parenteral nutrition decreased microsomal cytochrome P450 concentration (47%), p-nitroanisole demethylase activity (68%) and p-nitrophenol UDP-glucuronosyltransferase activity (58%). Cytosolic glutathione-S-transferase activity towards 1-chloro-2,4-dinitrobenzene decreased 29%. Sulfotransferase activity towards p-nitrophenol and acetaminophen was decreased 48% and 25%, respectively. CONCLUSION: Lipid-free, total parenteral nutrition depresses drug conjugative metabolism in rats. The magnitude of this effect in humans remains to be investigated.

Acetaminophen↗
PubMedDate not supplied

Drug metabolizing enzyme changes after chronic buthionine sulfoximine exposure modify acetaminophen disposition in rats.

This study examined the effects of prolonged exposure to buthionine sulfoximine (BSO) on 1) the overall elimination pharmacokinetics of acetaminophen; 2) the sulfate and glucuronide conjugation processes primarily responsible for acetaminophen elimination; and 3) in vitro microsomal and cytoplasmic enzyme activities in rats. Rats imbibed drinking water containing 30 mM BSO for 6 days and then received an iv injection of acetaminophen, 150 mg/kg in a propylene glycol vehicle. Exposure to BSO, a specific inhibitor of gamma-glutamylcysteine synthetase, produced marked depletion of glutathione (GSH) and resulted in induction of hepatic UDP-glucuronosyltransferase and GSH-S-transferase enzyme activities, but not cytochrome P-450. BSO pretreatment had no effect on the total or renal clearance of acetaminophen in rats. However, BSO exposure increased the partial clearance of acetaminophen to acetaminophen glucuronide by 47% (1.29 +/- 0.08 vs. 1.90 +/- 0.23 ml/min/kg; p less than 0.01) and significantly (p less than 0.02) increased the percentage of the dose recovered as the glucuronide conjugate from 17.6 +/- 2.5 to 26.5 +/- 0.6 The partial clearance of acetaminophen to acetaminophen sulfate was decreased, although not significantly, from 4.46 +/- 0.62 to 3.39 +/- 0.82 ml/min/kg. BSO treatment increased microsomal UDP-glucuronosyltransferase activity toward three xenobiotic aglycones, p-nitrophenol, 1-naphthol, and morphine by 308, 61, and 66%, respectively (p less than 0.05), but not toward testosterone or estrone. Cytosolic GSH-S-transferase activity toward 1-chloro-2,4-dinitrobenzene was increased 52% by BSO, whereas p-nitrophenol sulfotransferase activity was not altered. Cytochrome P-450 concentration and monooxygenase activity were unchanged by BSO exposure.

Acetaminophen↗
PubMedDate not supplied

Dose dependence in the plasma pharmacokinetics and uptake kinetics of 2',3'-dideoxyinosine into brain and cerebrospinal fluid of rats.

Dose dependence in the plasma pharmacokinetics of 2',3'-dideoxyinosine (ddI) was examined during and after 2-hr iv infusions in rats at infusion rates of 12.4, 32.7, and 125 mg/kg/hr. After termination of the infusions, the disappearance of ddI from plasma was distinctly biphasic, suggesting that the majority of ddI is eliminated before distribution equilibrium is achieved. The mean alpha t1/2 following the infusions was 2.7 min and was independent of dose. The mean terminal half-life (beta t1/2) was approximately 24 min and also independent of dose. Nonlinear pharmacokinetic behavior in plasma after infusions was manifested in a decreased clearance with increasing dose, as determined from steady state plasma concentrations of ddI during infusions. In parallel with the decreased clearance, the apparent volume of distribution of the central compartment, Vcapp, decreased with increasing dose. Nonlinearity in clearance with increasing dose could be accounted for using a model which includes rapid, saturable tissue binding. Dose dependence in the kinetics of uptake of ddI into brain tissue and cerebrospinal fluid (CSF) was also examined during and after iv infusions. Steady state concentrations of ddI in brain tissue and CSF varied linearly with steady state plasma concentrations over a plasma concentration range of greater than 30-fold. Mean tissue to plasma concentration ratios, expressed as percentages, were 2% in CSF, 5% in brain tissue, and 1-2% in brain parenchymal tissue (corrected for the contribution of the cerebral vascular space).

Animals↗
PubMedDate not supplied

Suppression of acetaminophen conjugation and of conjugate elimination in the rat by metyrapone, a classical P-450 inhibitor.

This study examined the effects of metyrapone on the overall elimination of acetaminophen and on the individual processes principally responsible for elimination, the formation of acetaminophen sulfate and glucuronide. Because acetaminophen pharmacokinetics are nonlinear above a threshold dose, experiments were designed to investigate acetaminophen elimination in the linear (30 mg/kg) and nonlinear (150 mg/kg) ranges to assess possible effects of metyrapone on conjugating enzymes and on cofactor availability. Prior treatment with 400 mg/kg metyrapone tartrate decreased total clearance of acetaminophen over 30% in the linear range (25.4 +/- 2.0 vs. 36.2 +/- 3.7 ml/min/kg in controls; p less than 0.01) and over 40% in the nonlinear range of disposition (4.42 +/- 1.07 vs 7.76 +/- 1.37 ml/min/kg in controls, p less than 0.01). Partial clearance to acetaminophen glucuronide was decreased by metyrapone in each dose range. Partial clearance to acetaminophen sulfate also declined in each dose range but statistically so only after 150 mg/kg. Metyrapone decreased the renal clearance of acetaminophen sulfate and glucuronide when these conjugates were formed in vivo after acetaminophen administration. However, metyrapone failed to impair the renal clearance of acetaminophen glucuronide when preformed metabolites were administered directly. The utility of metyrapone as a specific inhibitor of oxidative drug metabolism appears to be limited for drugs such as acetaminophen by concomitant inhibition of competing conjugation pathways, which account for the majority of drug elimination.

Acetaminophen↗