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M Vore

Publications and source records attributed to M Vore.

At least 73 records · Page 4Linked to original sources
PubMed1984

Characterization of uptake of steroid glucuronides into isolated male and female rat hepatocytes.

The uptake of estradiol-17 beta(beta-D-glucuronide) (E(2)17G), estriol-16 alpha(beta-D-glucuronide (E(3)16G), estradiol-17 beta-3-(beta-D-glucuronide) (E(2)3G) and taurocholate (TC) into hepatocytes isolated from male and female rats was examined and found to be linear for at least 75 sec and to exhibit Michaelis-Menten kinetics. The Vmax (nanomoles per minute per milligram of protein) for uptake in female rat hepatocytes ranged from 0.56 for TC to 2.32 for E(3)16G and from 0.89 for TC to 1.62 for E(2)17G in males. For TC, E(2)17G and E(2)3G, the Vmax for uptake was the same or higher in males, whereas for E(3)16G the Vmax was approximately 2-fold higher in females. The Km for TC was approximately equal in males and females, whereas for E(2)17G and E(3)16G, males exhibited a 3- to 9-fold lower Km. The rate of uptake of E(2)17G (100 microM) was decreased in the presence of carbonylcyanide-m-chlorophenylhydrazone (23%), 2,4-dinitrophenol (54%), potassium cyanide (38%), iodoacetic acid (46%) and rotenone (50%) and was reduced by 30 to 40% when sodium was replaced with lithium or choline or in the presence of ouabain. The rate of uptake of all the organic anions was reduced by 80 to 85% at 0-4 degrees C and the cell/medium concentration ratios at 75 sec (37 degrees C) exceeded 1. Thus, the steroid glucuronides are taken up by the hepatocyte by a saturable process; E(2)17G uptake was found to be partially dependent upon metabolic energy and an intact sodium gradient. Substrate-dependent differences in the rate of uptake between male and female rat hepatocytes were also seen.

Animals↗
PubMed1984

Gas-chromatographic quantification of methylphenidate in plasma with use of solid-phase extraction and nitrogen-sensitive detection.

The gas-chromatographic assay for methylphenidate described here involves isolation by solid-phase extraction and quantification by thermionic nitrogen-phosphorus detection. Methylphenidate and the internal standard, ethylphenidate, are extracted from plasma by partition onto C2 reversed-phase packing. Methylphenidate and ethylphenidate are eluted, dried, derivatized with trifluoroacetic anhydride, and gas-chromatographed, with nitrogen-sensitive detection. The standard curve for the assay is linear in the range 5-100 micrograms/L. The within-run CV is less than 4%, the between-run CV less than 6%. Mean analytical recovery of methylphenidate was greater than 90%. The smallest measurable concentration is 2 micrograms/L. The sensitivity, reproducibility, and economy of this assay make it suitable for clinical monitoring and pharmacokinetic studies.

Child↗
PubMed1983

Ethynylestradiol-17 beta D-ring glucuronide conjugates are potent cholestatic agents in the rat.

17 alpha-Ethynylestradiol-17 beta (beta-D-glucuronide) [EE217 beta (beta G)], a metabolite of 17 alpha-ethynylestradiol (EE2) identified in urine of women taking EE2 in oral contraceptives, and its synthetic anomer, 17 alpha-ethynylestradiol-17 beta (alpha-D-glucuronide), [EE217 beta (alpha G)], were administered intravenously to female rats in order to determine their effects on bile flow. Both agents induced an immediate, profound and dose-dependent decrease in bile flow which returned to control levels within 1-8 hr. The logarithm of the dose vs the cholestatic response curves for the two anomers were not parallel. EE217 beta (alpha G) was significantly more potent than EE217 beta (beta G) such that the doses inhibiting bile flow by 50% were 1.25 and 11 mumol/kg for the alpha-and beta-anomer respectively.

Animals↗
PubMed1983

Steroid D-ring glucuronides: characterization of a new class of cholestatic agents.

In summary, we have shown that steroid D-ring, but not steroid A-ring, glucuronide conjugates act at the level of the bile canaliculus to decrease bile-acid-dependent flow, initially; and subsequently, bile-acid-independent flow. These data indicate that glucuronide conjugates are not necessarily inactive; the present glucuronides clearly possess toxicological activity. The cholestatic glucuronides are all natural, endogenously formed products of metabolism. The critical questions which remain are whether metabolism of steroids to D-ring glucuronides is an obligatory step in the etiology of steroid-induced cholestasis and whether these glucuronides, at concentrations attained in humans, are capable of decreasing hepatic excretory function and inducing morphological and biochemical changes of clinical importance.

Animals↗
PubMed1983

Hepatotoxic effects of estradiol-17 beta-D-glucuronide in the rat and monkey.

The steroid D-ring glucuronide conjugate estradiol-17 beta-D-glucuronide (E217G) but not the A-ring conjugate E23-glucuronide (E23G) has been shown to inhibit bile flow in the rat. To determine if primates are also sensitive to E217G-induced cholestasis, a noninvasive approach with the use of indocyanine green (ICG), a dye eliminated primarily by biliary excretion, was first validated in the rat and then applied to the rhesus monkey. ICG (16 mg/kg rat; 4 mg/kg monkey) was administered i.v. 10 min after an i.v. bolus dose of either E217G (5.5 or 11 mumol/kg), E23G (11 mumol/kg) or vehicle alone. In the rat, the elimination T1/2 of ICG was increased by the 11 mumol/kg dose of E217G (P less than .025), whereas E23G produced no significant change from vehicle control values. In the monkey, the 5.5 and 11 mumol/kg doses of E217G increased the T1/2 of ICG in a dose-related manner (P less than .005), whereas E23G was without effect. Plasma levels of total radioactivity demonstrated dose-dependent kinetics after the administration of a tracer dose and 11 mumol/kg of [3H]E217G. A rebound of plasma radioactivity was seen at 11 mumol/kg of [3H] E217G, the time course of which mimicked the time course of E217G-induced cholestasis. High-performance liquid chromatographic analysis of rat bile and plasma after the administration of [3H]E217G revealed primarily E217G and estradiol-3-sulfate-17 beta-D-glucuronide together with small amounts of three unidentified metabolites. In the monkey, only E217G and estradiol-3-sulfate-17 beta-D-glucuronide were observed in the plasma after the administration of [3H]E217G. In contrast to E217G, estradiol-3-sulfate-17 beta-D-glucuronide was choleretic in the bile duct-cannulated rat model. These data indicate that E217G is hepatotoxic in both rodents and nonhuman primates.

Animals↗
PubMed1981

Steroid D-ring glucuronides: characterization of a new class of cholestatic agents in the rat.

Estriol-17 beta(beta-D-glucuronide) (E317G), estriol-16 alpha(beta-D-glucuronide) (E316G) and testosterone-17 beta(beta-D-glucuronide) (TG) produced an immediate, reversible and dose-dependent inhibition of bile flow after their i.v. administration in the rat. Within 15 to 30 min of their administration, bile flow was inhibited by 50% at doses of 13.2, 20.0 and 31.6 mumol/kg of E317G, TG and E316G, respectively. A plot of the logarithm of the dose of each agent vs. the maximal percentage of inhibition of bile flow yielded straight lines which were parallel. E317G, TG and E316G were 0.68, 0.40 and 0.29 times as potent, respectively, as estradiol-17 beta(beta-D-glucuronide), a previously identified cholestatic steroid glucuronide. Maximal inhibition of bile acid secretory rate was similar to that of bile flow for all three agents. Calculation of the bile acid vs. bile flow regression lines indicated substantial inhibition of bile acid independent flow by E317G and TG but only slight inhibition by E316G. In contrast, estriol-3(beta-D-glucuronide) at doses of 11 and 33 mumol/kg increased bile flow. After an i.v. dose (44 mumol/kg) of [3H]E316G, 53% of the dose was recovered in the bile in 3 hr. Unchanged [3H]E316G and a minor metabolite tentatively identified as [3H]estriol-3-sulfate-16 alpha(beta-D-glucuronide) were the predominant compounds recovered in the bile. These data present evidence for a new class of cholestatic compounds, the steroid D-ring glucuronides, and suggest a means by which endogenous or exogenous steroids may produce hepatobiliary dysfunction.

Animals↗
PubMed1980

Characterization of cholestasis induced by estradiol-17 beta-D-glucuronide in the rat.

Estradiol-17 beta-D-glucuronide induced an immediate, profound and reversible inhibition of bile flow after its i.v. administration in the rat. The degree of cholestasis was dose-dependent in the range of 8.5 to 21 mumol/kg i.v. A dose of 11 mumol/kg i.v. inhibited bile flow and bile acid secretory rate 65 to 70% within 15 to 30 min of its administration; bile flow and bile acid secretion had returned to near control values within 3 hr. Linear regression analysis of the relationship between bile flow and bile acid secretion indicated a substantial decrease in bile acid independent flow. In contrast, neither estradiol-17 beta, estradiol-3-glucuronide nor estradiol-3-sulfate-17 beta-D-glucuronide at an equimolar dose had any inhibitory effect on these parameters. After a dose of [3H]estradiol-17 beta-D-glucuronide, 79% of the administered radioactivity was excreted in the bile in 3 hr. Estradiol-3-sulfate-17 beta-D-glucuronide was tentatively identified as the predominant biliary metabolite with estradiol-17 beta-D-glucuronide also present in substantial amounts. These data indicate that estradiol-17 beta-D-glucuronide is toxicologically active and suggest the possibility that this estrogen metabolite may induce hepatic pathology in vivo.

Animals↗
PubMed1980

The effect of estradiol-17 beta treatment on the metabolism and biliary excretion of phenytoin in the isolated perfused rat liver and in vivo.

The metabolism and biliary excretion of [14C]phenytoin (DPH) was examined in female control rats and in rats pretreated with estradiol-17 beta (E2) (1 mg/day s.c.) for 7 days. In the isolated perfused liver, the half-time of [14C]DPH in the perfusate was not altered by E2 treatment, nor was the rate of appearance and disappearance of 5-[14C]phenyl-5-para-hydroxyphenylhydantoin (HPPH), the major metabolite of DPH. Cumulative secretion of the glucuronide 4- and 6-fold, respectively, in E2-treated rats. Following administration of [14C]DPH (1 mg/kg i.v.) in vivo, the concentration of [14C]HPPH-glucuronide was significantly increased in the blood in E2-treated rats, although there was no significant decrease in the bile concentration or excretion rate of this metabolite. Bile flow averaged 50 and 35 microliters/min/kg in control and E2-treated rats, respectively. Following administration of [14C]HPPH (60 mg/kg i.v.) in vivo, the rate of disappearance of [14C]HPPH from the blood was increased in E2-treated rats. The concentration in bile (micromoles per milliliter) and biliary excretion rate (micromoles per minute per kilogram) of [14C]HPPH-glucuronide were significantly increased in E2-treated rats relative to controls. Maximal bile/blood concentration ratios of [14C]HPPH-glucuronide were 725 and 200 in control and E2-treated rats, respectively, indicating a decreased ability of the liver to concentrate the glucuronide conjugate in the bile following estrogen treatment.

Animals↗
PubMed1979

The effect of pregnancy on the biliary excretion of [14C]phenytoin in the rat.

The biliary excretion of [14C]phenytoin (DPH) was examined in pregnant and nonpregnant female control rats. After administration of [14C]DPH (1 mg/kg i.v.), the bile concentration (nanomoles per milliliter) and biliary excretion (nanomoles per minute per kilogram) of the glucuronide conjugate of the major primary metabolite of DPH, 5-phenyl-5-p-hydroxyphenyl[4-14C] hydantoin ([14C)]HPPH), was significantly decreased at 15 and 30 min in pregnant rats relative to controls. Bile flow averaged 50 and 70 microliter/min/kg in control and pregnant rats, respectively. The concentration in blood of [14C]HPPH-glucuronide was increased 2 to 6-fold in pregnant rats relative to controls. After administration of [14C]HPPH (10 mg/kg i.v.), the disappearance of [14C]HPPH from the blood, biliary excretion and bile concentration of [14C]HPPH-glucuronide were very similar in control and pregnant rats. The blood concentration of [14C]HPPH-glucuronide was elevated 2 to 6-fold in pregnant rats and the half-life was increased from 43 min in controls to 70 min in pregnant rats. Maximal bile/blood concentration ratios of [14C]HPPH-glucuronide were 630 and 300 in control and pregnant rats, respectively, indicating a decreased ability of the liver to concentrate the glucuronide in the bile in pregnancy.

Animals↗
PubMed1978

The effect of pregnancy on the metabolism of [14C]phenytoin in the isolated perfused rat liver.

The metabolism of [14C]phenytoin (DPH) was measured in isolated perfused livers from non-pregnant female rats and rats at 13, 15, 17, 19 and 21 days of gestation. The half-life of [14C]phenytoin in the perfusate was not significantly altered by pregnancy in livers perfused with 20% blood at 2 ml/min/g of liver but was increased from 38 min in control livers to 158 min in livers from rats at 21 days of gestation when livers were perfused with 10% blood at 1 ml/min/g of liver. Secretion of the glucuronide conjugate of 5-[14C]phenyl-5-parahydroxy-phenylhydantoin into the bile was markedly inhibited during the latter stages of pregnancy such that a 4-fold decrease in the cumulative secretion into the bile was present at 21 days of gestation. The bile/perfusate concentration ratio of the glucuronide after 30 min was 148 in control livers but decreased to 6 in livers from rats at 21 days gestation.

Animals↗