The metabolism of 1-n-butyl-5,5-diethylbarbituric acid (N-n-butyl barbital) in the rat.
Explore the source record for details and available documents.
Acetone↗
Biomedical subjects
M Vore
Publications and source records attributed to M Vore.
Oral contraceptives: a cause of hyperbilirubinemia in stem cell transplant patients.
Conjugated hyperbilirubinemia in the clinical setting of hematopoietic stem cell transplantation can have multiple etiologies that may prompt various therapeutic interventions. Two patients who received short courses of a high-dose estrogen-progesterone combination to treat breakthrough menstrual bleeding during transplant are reported. Conjugated hyperbilirubinemia developed in both patients within days of beginning therapy and resolved after the ethinyl estradiol and norgestrel (Ovral; Pharmacia and Upjohn, Kalamazoo, MI, U.S.A.) was discontinued. In one of the patients, this occurred on three separate occasions during the course of transplantation. Recognizing the cholestatic effect of estrogens during transplantation may prevent unnecessary alterations in therapy beyond the simple discontinuation of these medications.
Adolescent↗
Cholestatic properties and hepatic transport of steroid glucuronides.
In summary, the data suggest that E217G is transported by both MOAT and P-glycoprotein into bile, but that P-glycoprotein serves as the target site for cholestasis. We postulate that this target site may be accessed from either the intracellular compartment or the canaliculus, and that MOAT serves as the major delivery route for E217G to the canaliculus. At low, physiologic concentrations of E217G, MOAT-mediated excretion into bile is a detoxification mechanism, serving to prevent intracellular accumulation of a toxic metabolite. However, following administration of high, cholestatic doses, MOAT-mediated excretion into bile results in very high concentrations in bile, on the other of 2-3 mM (see Fig. 4). It is likely that the hydrophobic nature of E217G allows it to partition from bile into the canalicular membrane, from which it can access P-glycoprotein and thus induce cholestasis. Much work is still needed to validate this model of E217G cholestasis. Definitive evidence of P-glycoprotein-mediated transport of E217G must be obtained in cell lines transfected with P-glycoprotein where MRP is absent. More importantly, the mechanism by which interaction of E217G with P-glycoprotein influences bile flow is unknown. Higgins and colleagues have provided evidence that P-glycoprotein regulates a Cl- channel in a manner analogous to that of CFTR, the cystic fibrosis transmembrane conductance regulator. While Cl- channels have been shown to be important in the regulation of the volume of the hepatocyte in the presence of altered osmotic conditions, a role for this channel in bile flow has not been demonstrated. Nevertheless, these studies implicate a role of P-glycoprotein in the regulation of bile secretion by the liver.
Animals↗
Effects of taurocholate infusion on biliary excretion in isolated perfused rat livers. Decreased biliary excretion of dibromosulfophthalein in pregnancy.
A crossover experimental design was used to examine the effects of saline (SAL) vs. taurocholate (TC) infusion on hepatic excretory function in isolated perfused livers from pregnant (19-21 days gestation) and nonpregnant female rats. Bile flow, bile acid concentration, bile acid secretory rate, dibromosulfophthalein (DBSP) concentration in bile, and DBSP secretory rates were determined in livers infused continuously with DBSP and initially with SAL (1 ml/hr, 45 min), followed by TC (60 mumol/hr, 1 ml/hr; 75 min) or initially with TC (45 min) followed by SAL (75 min). The order of infusion (SAL-TC vs. TC-SAL) had no significant effect. TC infusion significantly increased all measures in livers from both nonpregnant and pregnant rats. Two-way analysis of variance followed by the Tukey-Kramer test showed that bile flow (microliter/min/g liver) and DBSP concentration in bile (mumol/ml) were significantly decreased during SAL infusions in pregnancy. These two measures plus bile acid and DBSP secretory rates (nmol/min/g liver) were also significantly decreased during TC infusion in pregnancy. Pregnancy had no effect on bile acid concentration in the presence of SAL or TC infusions. When bile flow, bile acid, and DBSP secretory rates were calculated per whole liver, only the DBSP secretory rate was significantly decreased in pregnancy. These data indicate that bile flow and bile acid secretion do not increase in proportion to the increase in liver weight in pregnancy so that these measures are decreased when expressed per g liver. Pregnancy appears to have a real inhibitory effect on DBSP since its secretion is depressed when activity is expressed per g liver or per whole organ.
Animals↗
Reductive metabolism of nitrofurantoin in the rat.
The reductive metabolism of nitrofurantoin under anaerobic conditions was characterized in various tissues from control, germ-free, and germ-free acclimatized rats. Nitrofurantoin metabolism was highest in homogenates of cecum and colon contents of germ-free acclimatized and control rats, but was absent from those of germ-free animals. Appreciable levels of activity were also present in homogenates of liver and of small intestine walls with lesser rates of metabolism observed in kidney homogenates. The major metabolite of nitrofurantoin, which was isolated and purified by high-pressure liquid chromatography, was identified as 1-[[(3-cyano-1-oxopropyl)-methylene]amino]-2,4-imidazolidinedione. A second, minor metabolite with high-pressure liquid chromatography and ultraviolet absorption characteristics similar to those of 1-[[(5-amino-2-furanyl)methylene]amino]-2,4-imidazolidinedione (aminofurantoin) was detected in cecum and colon contents.
Anaerobiosis↗
Hepatic estrone and estradiol glucuronyltransferase activity in pregnancy. Induction by pretreatment with 3-methylcholanthrene and phenobarbital.
Hepatic microsomal estrone and estradiol glucuronyltransferase activity were examined in nonpregnant female and pregnant rats and rabbits. Pregnancy decreased glucuronyltransferase activity towards both substrates by 30% in rats and rabbits when activity was expressed per mg of microsomal protein. Because of the increased size of the liver in pregnancy in the rat, activity was increased in this species when expressed per whole liver. The size of the liver was not increased in pregnancy in the rabbit, so that activity per whole liver was also decreased in this species. Pretreatment of nonpregnant rats with 3-methylcholanthrene had little effect on estradiol glucuronyltransferase activity and increased estrone glucuronyltransferase activity 35%. Similar pretreatment of pregnant rats, however, increased estradiol glucuronyltransferase activity approximately twofold and estrone glucuronyltransferase activity approximately threefold. Phenobarbital was a much less potent inducer of estrone and estradiol glucuronyltransferase activities but did increase activities to a greater extent in pregnant rats than in nonpregnant female controls.
Animals↗
Hepatic morphine and estrone glucuronyltransferase activity and morphine biliary excretion in the isolated perfused rat liver. Effect of pregnancy and estradiol-17 beta treatment.
Hepatic microsomal estrone and morphine glucuronyltransferase activity and the biliary excretion of morphine in the isolated perfused liver were examined in nonpregnant, pregnant (19-21 days of gestation), and estradiol-17 beta-treated (E2; 1.0 mg/kg/day sc for 14 days) rats. Pregnancy decreased estrone and morphine glucuronyltransferase activity 20%, whereas E2 treatment increased activity 50%. Treatment of nonpregnant and pregnant rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin (3 micrograms/kg po) increased estrone glucuronyltransferase activity 1.3- and 2.8-fold respectively, but such treatment had no effect in E2-treated rats. In the isolated perfused liver, E2 treatment, but not pregnancy, decreased the biliary excretion of morphine 3-glucuronide. Bile flow (microliter/min/g of liver) was slightly decreased by pregnancy but not by E2 treatment. Maximal bile/perfusate concentration ratios of morphine glucuronide were 175, 325, and 90 in livers from nonpregnant, pregnant, and E2-treated rats, respectively.
Animals↗
The effect of pregnancy and estradiol-17 beta treatment on the biliary transport maximum of dibromosulfophthalein, and the glucuronide conjugates of 5-phenyl-5-p-hydroxyphenyl[14C]hydantoin and [14C]morphine in the isolated perfused rat liver.
The biliary transport maximum (Tm) of three organic axions was determined in the isolated perfused livers of untreated female (control), estradiol-17 beta (E2)-treated female (1 mg/kg/day, s.c. for 14 days), and pregnant (19-21 days of gestation) rats. Dibromosulfophthalein (DBSP), 5-phenyl-5-p-hydroxyphenyl[14C]hydantoin (HPPH) and [14C]morphine were infused continuously into the perfusate for a total dose of 41.2, 18, or 40.5 mumol, respectively. The concentration of [14C]HPPH and [14C]morphine declined in the perfusate, whereas the concentrations of [14C]HPPH glucuronide and [14C]morphine glucuronide increased during the 90-min experiment, indicating that the rate of formation of the glucuronide exceeded its rate of excretion in bile. E2 treatment decreased the Tm (nmol/min/g liver) for [14C]HPPH glucuronide and [14C]morphine glucuronide but not for DBSP, whereas pregnancy decreased the Tm for all three organic anions. Pregnancy, and to a lesser extent E2 treatment, increased liver weight. When expressed per whole liver, the Tm was not altered by pregnancy for any of three organic anions. E2 treatment increased the Tm for DBSP, had no effect on the Tm for HPPH glucuronide and decreased the Tm for [14C]morphine glucuronide. These data suggest the presence of multiple carriers for organic anions which are differentially affected by estrogen treatment and pregnancy.
Animals↗
The effect of pregnancy and treatment with 17 beta-estradiol on the transport of organic anions into isolated rat hepatocytes.
The uptake of the bile acid taurocholate (TC), and the organic anions, estradiol-17 beta (beta-D-glucuronide) (E217G), estradiol-3-(beta-D-glucuronide) (E23G), estriol-16 alpha (beta-D-glucuronide) (E316G), and morphine glucuronide (MG) were evaluated in hepatocytes isolated from nonpregnant female, pregnant (19-21 days of gestation) and E2-treated (1 mg/kg/day sc for 14 days) rats. Pregnancy significantly decreased the uptake of TC, E217G, E23G, and MG whereas E2 treatment decreased only the uptake of E217G. The Vmax (nmol/min/mg protein) for E217G uptake was significantly decreased from 1.45 +/- 0.2 (mean +/- SE) in hepatocytes from nonpregnant female rats to 0.70 +/- 0.11 and 0.64 +/- 0.13 in cells from pregnant and E2-treated rats, respectively. The Vmax for uptake of TC was decreased, but not significantly, from 0.56 +/- 0.16 in hepatocytes from nonpregnant female rats to 0.34 +/- 0.08 in cells from pregnant rats.
Animals↗