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Biomedical subjects

S Schenker

Publications and source records attributed to S Schenker.

At least 109 records · Page 6Linked to original sources
PubMed1984

Mephenytoin hydroxylation deficiency: kinetics after repeated doses.

Deficient aromatic hydroxylation of S-mephenytoin was observed in an index subject during a kinetic study of stereoselective metabolism of mephenytoin. A genetic basis for this defect was suggested by decreased urinary recovery of 3-methyl-5-(4-hydroxyphenyl)-5-ethylhydantoin (4-OH-M) in the 24 hr after oral racemic mephenytoin in two brothers of the propositus. The parents and a third brother had urinary recoveries of 4-OH-M of the same order as in a group of 20 normal subjects. The kinetic implications of this defect were studied in the index subject and compared with four normal subjects after a single oral dose of differentially radiolabeled pseudoracemic mephenytoin (5 microCi of 14C-S-mephenytoin, 45 microCi of H3-R-mephenytoin, and 11.5 mumol/kg of both S- and R-mephenytoin) followed by single oral doses of 1.4 mmol of unlabeled racemic mephenytoin daily the next 4 days. In normal subjects, there was substrate stereoselective metabolism with the S-enantiomer rapidly excreted as 4-OH-M and the R-enantiomer slowly excreted as 5-phenyl-5-ethylhydantoin (PEH). Stereoselective metabolism persisted during repeated dosing. In the hydroxylation-deficient subject, there was no evidence of stereoselective metabolism, recovery of 4-OH-M was low, and both enantiomers were slowly excreted, predominantly as PEH. Plasma PEH concentrations and urinary PEH excretion rates were approximately twice that in normal subjects. Thus a genetic deficiency in ability to hydroxylate S-mephenytoin results in the S-enantiomer metabolization by the alternate route of demethylation to PEH that cumulates, thereby, in comparison to the normal, effectively doubling the dose of total hydantoin.

Adult↗
PubMed1984

Diphenhydramine disposition in chronic liver disease.

Diphenhydramine (DPHM) disposition was examined in nine patients with chronic alcohol-related liver disease and in eight normal subjects. Sleep of 1 to 2 hr duration was induced in all subjects by a 0.8 mg/kg iv dose without an apparent increase in cerebral sensitivity in the patients with cirrhosis. Protein binding as determined by equilibrium dialysis (3H-DPHM) revealed a 15% decrease in the cirrhotic patients, while recovery of unchanged DPHM in urine (2%) was of the same order in the two groups. Computerized biexponential curve analysis was used to compare the plasma profiles for five of the patients and six of the normal subjects. Monoexponential curve analysis of the terminal beta-phase, including all subjects, was also used to compare the two groups. The means of plasma clearance and apparent volume of distribution in cirrhotic patients were respectively less and greater than in normal subjects, but these differences were not significant. The t1/2 for the beta-phase (t1/2 beta), which reflects this reciprocal trend, was increased in the patients (15.2 +/- 1.5 and 9.3 +/- 0.9 hr). This correlated in part with severity of disease, with r = 0.723 between t1/2 beta and the serum bilirubin levels. In conclusion, a single intravenous dose of DPHM provided safe and effective sedation in patients with cirrhosis.

Adult↗
PubMed1984

Effects of ethanol and/or caffeine on fetal development and placental amino acid uptake in rats.

The effects of ethanol alone or in combination with caffeine on fetal viability, growth and placental amino acid uptake function in the rat were examined. Compared to pair-fed control values, chronic ethanol exposure reduced fetal survival by 24%, fetal weight by 17%, along with weight decreases of fetal brain (16%), heart (31%), and kidney (48%) as compared to pair-fed control values. Placental weight was significantly increased by 17%. Concomitant caffeine intake generally exacerbated these effects with a further reduction in fetal survival, fetal body and visceral weights. Caffeine intake alone had no consistent effect on these parameters. Acute in vitro (3 mg/ml) and chronic in vivo ethanol exposure reduced placental net uptake of alpha-aminoisobutyric acid (AIB) by 32 and 45%, respectively. Neither acute in vitro (10 micrograms/ml) nor prior chronic caffeine exposure altered villous AIB uptake. Concomitant ethanol and caffeine treatment increased AIB uptake as compared to ethanol alone. However, AIB uptake continued to be reduced (by 22%) as compared to pair-fed control values.

Amino Acids↗
PubMed1984

Selective inhibition of acetaminophen oxidation and toxicity by cimetidine and other histamine H2-receptor antagonists in vivo and in vitro in the rat and in man.

Acetaminophen-induced hepatotoxicity results from hepatic enzymatic oxidation of acetaminophen to a toxic, electrophilic intermediate. Acetaminophen is ordinarily eliminated after conjugation with glucuronic acid and sulfate to nontoxic derivatives. Cimetidine has been shown to inhibit the hepatic oxidation of a number of drugs and to protect rats from acetaminophen-induced hepatic necrosis. The aim of this study was to define the mechanism by which cimetidine reduced acetaminophen-induced hepatic necrosis and to determine whether inhibition of formation of the reactive metabolite(s) of acetaminophen occurred also in man. In vivo cimetidine pretreatment decreased covalent binding of [3H]acetaminophen to the liver from 552 +/- 23.8 to 170 +/- 31.6 nmol/g protein 2 h after a toxic dose of acetaminophen in 3-methylcholanthrene pretreated rats (P less than 0.05). Cimetidine pretreatment also significantly reduced the rate of hepatic glutathione depletion. Both cimetidine and metiamide produced dose-dependent inhibition of acetaminophen oxidation in vitro, whereas inhibition by ranitidine and cimetidine sulfoxide was quantitatively less. Inhibition of acetaminophen oxidation by cimetidine and metiamide was primarily competitive with an inhibition constant (Ki) of 130 +/- 16 and 200 +/- 50 microM, respectively. By contrast, cimetidine inhibited acetaminophen glucuronidation minimally with a Ki of 1.39 +/- 0.23 mM. Similar results were obtained using human liver microsomes as a source of enzymes. In a dose-related fashion, cimetidine also reduced acetaminophen-induced toxicity to human lymphocytes when incubated with microsomes and NADPH. Pharmacokinetics of acetaminophen elimination were studied in normal volunteers with and without co-administration of cimetidine 300 mg every 6 h. In normal volunteers, cimetidine decreased the fractional clearance of the oxidized (potentially toxic) metabolites of acetaminophen more than the conjugated metabolites. This finding confirmed the hypothesis that cimetidine is a relatively selective inhibitor of the oxidation of acetaminophen to reactive metabolites in man as well as in animals. When considered together with the results of previous studies showing improved survival and decreased hepatoxicity in acetaminophen-poisoned animals, the present results provide a rational basis for assessing possible benefits of cimetidine treatment of acetaminophen overdoses in man.

Acetaminophen↗
PubMed1984

The pharmacokinetic interaction of diethyl ether with aminopyrine in the rat.

Our studies in rats clearly demonstrate a significant depression of aminopyrine metabolism in vivo by ether anesthesia. The depression of aminopyrine elimination was shown both by measurements of plasma aminopyrine clearance and by depression of the [14C]aminopyrine breath test. No apparent effect of ether was seen on aminopyrine volume of distribution. The effect of ether was prolonged, as judged by its persistence in the aminopyrine breath test for 3 hr after stopping ether anesthesia. In addition, when ether was administered in combination with a single dose of ethanol, aminopyrine clearance was inhibited significantly more than with ethanol alone. These data not only have a bearing on proper methodologic design of drug clearance studies but also may relate to the effects of some anesthetics on hepatic function.

Aminopyrine↗
PubMed1984

Clearance and metabolism of plasma pyridoxal 5'-phosphate in the dog.

This study was undertaken to characterize the metabolic fate of plasma pyridoxal 5'-phosphate (pyridoxal-P), the role of various organs in mediating its degradation, and the contribution of urinary excretion. Anesthetized dogs underwent sham operation, hepatectomy, nephrectomy, or combined surgical removal of the stomach, small intestine, and the spleen; however, the kinetics of plasma pyridoxal-P clearance after the intravenous administration of 2.5 mg of this B6 vitamin were not altered. In anesthetized sham-operated dogs and in unanesthetized dogs, pyridoxal (product of pyridoxal-P hydrolysis) but not 4-pyridoxic acid (oxidation product of pyridoxal) accumulated in plasma and urine after pyridoxal-P administration. Urinary excretion of pyridoxal-P was negligible and it could not account for the rapid clearance of pyridoxal-P from the plasma. The rate of pyridoxal-P hydrolysis mediated by plasma alkaline phosphatase and the cellular elements in whole blood in vitro was also too slow to account for the rapid disappearance of plasma pyridoxal-P in vivo. These results indicate that (1) normally, the overall capacity of the body to hydrolyze circulating pyridoxal-P in plasma is so large that removal of the liver, kidneys, or the intestinal tract and spleen has little or no effect on the rate of plasma pyridoxal-P decay; and (2) plasma pyridoxal-P decay normally proceeds by way of hydrolysis to form pyridoxal. Because pyridoxal is not further oxidized by the liver and the amount of pyridoxal excreted in the urine accounts for less than 25% of the pyridoxal that can be derived from the injected pyridoxal-P load, the preponderant metabolic fate of plasma pyridoxal-P most likely involves its hydrolysis to pyridoxal and then the uptake of pyridoxal by extrahepatic tissues.

Alkaline Phosphatase↗
PubMed1984

Stereoselective metabolism and pharmacogenetic control of 5-phenyl-5-ethylhydantoin (nirvanol) in humans.

Aromatic hydroxylation of 5-phenyl-5-ethylhydantoin (PEH) has been investigated in humans. Single oral doses of S-PEH (247 mumol) were given to seven extensive and seven poor hydroxylators of mephenytoin. Urinary recovery of PEH and 5-(4-hydroxyphenyl)-5-ethylhydantoin (4-OH-PEH) indicated that all extensive metabolizer subjects excreted appreciable quantities of 4-OH-PEH, whereas all poor metabolizer subjects had only trace amounts of 4-OH-PEH in their urine. Four extensive metabolizer subjects received dual radiolabeled (S-[14C]PEH, R-[3H]PEH) pseudoracemic (494 mumol R-PEH, 494 mumol S-PEH) PEH and had serial urine and blood samples collected over 16 days. The urinary excretion rates of S-PEH and S-4-OH-PEH had half-lives of approximately 4.5 days whereas those of R-PEH and R-4-OH-PEH were approximately 10 days. The initial S/R ratio of 4-OH-PEH in urine was 14:1 whereas that of PEH was 1:1. Stereoselective hydroxylation in these four subjects was confirmed by the negligible recovery of 4-OH-PEH after oral administration of R-PEH (494 mumol). After racemic administration, the sum of S-and R-PEH plasma concentrations declined biexponentially with half-lives of the alpha- and beta-phases being consistent with the total plasma concentration reflecting the sum of the different rates of elimination of the two enantiomers. These results are consistent with the hypothesis that the same drug metabolizing enzymes are involved in the aromatic hydroxylation of S-mephenytoin and S-PEH.

Adolescent↗
PubMed1983

Effects of oral contraceptive steroids on acetaminophen metabolism and elimination.

Plasma acetaminophen elimination was examined in women taking low-dose estrogen oral contraceptive (OC) steroids and in age-matched control women. Fractional rates of elimination and fractional clearances were calculated for each of the metabolic pathways, including oxidation, sulfation, and glucuronidation. The cysteine adduct and mercapturic acid derivative of acetaminophen were used as an index of oxidative biotransformation, a potentially toxic route of metabolism for acetaminophen. Plasma acetaminophen clearance rose from 287 +/- 13 ml/min to 470 +/- 51 ml/min in women taking OC steroids, whereas elimination t1/2 decreased from 2.40 +/- 0.14 hr to 1.67 +/- 0.16 hr. The fractional clearance and rate of elimination of acetaminophen by glucuronidation increased in women taking OC steroids, whereas the clearance and elimination by sulfation did not differ significantly from values in control subjects. Fractional clearance of the cysteine adduct also increased significantly, but clearance of acetaminophen mercapturic acid did not change. These data suggest that the increased clearance of acetaminophen from plasma in women taking OC steroids results from increased glucuronidation of the drug, although the mechanism is not known.

Acetaminophen↗
PubMed1983

Periportal localization of lorazepam glucuronidation in the isolated perfused rat liver.

The relative effects of pretreatment with allyl alcohol and carbon tetrachloride on oxidative and glucuronide metabolism of lorazepam have been compared in the isolated perfused rat liver. Livers from rats pretreated for 24 hr with allyl alcohol (1.8 ml/kg, 1:50 solution, to induce pericentral hepatic necrosis), carbon tetrachloride (0.8 mg/kg in corn oil, to induce perivenular hepatic necrosis), or vehicle were perfused with 20% rat blood, 80% Krebs bicarbonate buffer at 20 ml/min. After 300 micrograms of lorazepam had been added to the reservoir, perfusate concentrations of lorazepam were measured in the perfusate at timed intervals. After 180 min, lorazepam and lorazepam glucuronide were measured in perfusate, bile, and liver homogenate. Allyl alcohol and carbon tetrachloride lowered lorazepam clearance by 47% and 77%, respectively. Recovery of lorazepam glucuronide after 180 min was lowered by 35% by treatment with allyl alcohol and increased 73% by treatment with carbon tetrachloride. Glucuronide recovery permitted estimation of fractional glucuronide vs. nonglucuronide clearance. In control rats, glucuronide clearance accounted for 25% of total clearance. Allyl alcohol caused a 64% reduction in glucuronide clearance but only a 39% reduction in nonglucuronide clearance. In contrast, carbon tetrachloride caused a 60% reduction in glucuronide clearance but an 83% reduction in nonglucuronide clearance. The differences in ratios of the changes in glucuronide and nonglucuronide clearance provide further circumstantial evidence that is consistent with the hypothesis of predominant periportal localization of glucuronidation and pericentral localization of oxidative metabolism of lorazepam.

Allyl Compounds↗
PubMed1983

Inhibition of caffeine elimination by short-term ethanol administration.

Short-term ethanol ingestion has been shown to inhibit the metabolism of a number of drugs metabolized by cytochrome P-450 in both man and laboratory animals. However, the effects of short-term ethanol administration on the metabolism of cytochrome P-448-dependent drugs in man is unknown. Caffeine is a commonly used drug that is metabolized predominantly by a component of the hepatic microsomal mixed-function oxidase complex, known as cytochrome P-448. Therefore the elimination of caffeine given orally was studied in normal volunteers after receiving either orange juice or 0.8 gm/kg ethanol as a 25% solution in orange juice. Short-term administration of ethanol resulted in a significant decrease in the plasma clearance of caffeine from 96.6 +/- 13.4 ml/min to 60.7 +/- 10.5 (mean +/- S.E., p less than 0.05). There was also a corresponding significant increase in the elimination half-life of caffeine from 4.03 +/- 0.52 hr to 6.04 + 0.73 (mean + S.E., p less than 0.01). To determine whether the decrease in caffeine elimination was due to an inhibition of caffeine metabolism by ethanol or to an effect on caffeine absorption, caffeine disposition was studied in four healthy, mongrel dogs after intravenous administration. Each animal served as its own control. Caffeine clearance decreased significantly from a baseline value of 19.6 +/- 1.5 ml/min to 8.0 +/- 1.5 (mean +/- S.E., p less than 0.05) after administration of 3.0 gm/kg ethanol given orally 1 hr before intravenous caffeine injection. These results imply that short-term administration of ethanol inhibits the metabolism of caffeine, a predominantly cytochrome P-448-dependent substrate, in both man and dogs.

Adult↗
PubMed1982

Differential effects of chronic ethanol feeding on cytochrome P-448- and P-450-mediated drug metabolism in the rat.

The effects of chronic ethanol feeding on cytochrome P-448- and P-450-mediated drug metabolism have been studied both in vivo and in vitro in the rat, using caffeine, phenacetin, antipyrine and aminopyrine as test substrates. N-Demethylation of aminopyrine (P-450 mediated) was increased both in vivo and in vitro in rats after chronic ethanol feeding (P less than 0.05) whereas in vivo N-demethylation of caffeine and O-dealkylation of phenacetin (P-448 mediated) were unchanged in the same animals. N-Demethylation of antipyrine was increased by both phenobarbital and 3-methylcholanthrene pretreatment and by chronic ethanol feeding (P less than 0.05), possibly due to cytochrome P-450 induction. Furthermore, the Michaelis affinity constants, Km, for hepatic microsomal aminopyrine N-demethylase and antipyrine N-demethylase were lower in chronic ethanol-fed animals (P less than 0.05), suggesting a qualitative change in the enzymes resulting in greater substrate affinity. These findings suggest a differential effect of chronic ethanol feeding on the induction of cytochrome P-450- and cytochrome P-448 mediated drug metabolism, with a greater effect on the former microsomal system.

Aminopyrine N-Demethylase↗
PubMed1982

Inhibition of placental amino acid uptake in rats following acute and chronic ethanol exposure.

The effects of acute and chronic maternal ethanol consumption on in vitro placental uptake of alpha-aminoisobutyric acid (AIB), cycloleucine, L-alanine (Ala), L-leucine (Leu), and L-lysine (Lys) were determined. Ethanol (4 g/kg. po) administered 2 hr prior to sacrifice, reduced (p less than 0.05) placental villous net uptake of cycloleucine and Ala by 29%. Prior chronic ethanol consumption depressed (p less than 0.05) placental uptake of AIB (38%), cycloleucine (45%), Ala (35%), Leu (25%), and Lys (34%). In vitro exposure of previously untreated villous fragments for 2 hr to 2 mg/ml of ethanol reduced (p less than 0.05) the net uptake of AIB and cycloleucine by 24% and 31%, respectively, whereas the minimum concentration of acetaldehyde required to cause a significant inhibition was 310 microM for AIB and 465 microM for cycloleucine. Ethanol (3 mg/ml) had no effect on AIB or cycloleucine net uptake if sodium was omitted from the incubation media. The efflux of AIB (10(-6)M) and cycloleucine (10(-6)M) from villous tissue was unaffected (p less than 0.05) by either ethanol (3 mg/ml) or acetaldehyde (600 microM) and obeyed first order kinetics. It was concluded that acute, and especially chronic, maternal ethanol consumption can depress the placental uptake of a variety of amino acids in the rat and, in the acute setting, the effect was on a sodium-dependent system involved in amino acid influx into placental cells.

Acetaldehyde↗
PubMed1982

Inhibition of microsomal drug metabolism by histamine H2-receptor antagonists studied in vivo and in vitro in rodents.

Cimetidine has been demonstrated to impair microsomal oxidative drug metabolism in a dose-dependent manner in an animal model. The inhibition has also been shown to be rapid, occurring after a single dose. In the present study we demonstrate that recovery from inhibition after cimetidine withdrawal is also rapid, occurring within 24 h. Furthermore, chronic dosing with cimetidine does not result in tolerance to the inhibitory effect. Other H2-antihistamines have also been studied both in vivo and in vitro. Based on spectral binding changes, in vitro enzyme assays and in vivo aminopyrine breath tests, ICI 125,211, ranitidine, and cimetidine sulfoxide are much less inhibitory than cimetidine. The ability of cimetidine to impair the elimination of aminopyrine in the mouse after acute liver damage was greater than in the normal mouse.

Aminopyrine↗