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Biomedical subjects

A Rane

Publications and source records attributed to A Rane.

At least 199 records · Page 11Linked to original sources
PubMed1984

Kinetics of 11C-labeled opiates in the brain of rhesus monkeys.

The regional uptake in the brain of Rhesus monkeys of i.v. administered 11C-labeled morphine, codeine, heroin and pethidine was studied by means of positron emission tomography. The technique measures the sum of parent drug and radiolabeled metabolites. (For the sake of simplicity the drug derived radioactivity is denoted by the drug name.) Morphine had a limited uptake to discrete areas of the brain. The maximum normalized uptake, with respect to dose per kilogram body weight, was about 0.2, i.e., 20% of the calculated activity if the drug had been evenly distributed throughout the body of the monkey. Maximum radioactivity appeared 30 to 45 min after injection. Morphine left the brain slowly with an estimated half-life of more than 2 hr. An area with a normalized uptake of about 1.0 was detected centrally in the lowest horizontal transsection of the skull. The origin of this area was identified as the pituitary. Codeine, heroin and pethidine were taken up to the brain to a larger extent than morphine, with maximum normalized uptakes of 2.6, 4.6 and 6.3, respectively. Maximum radioactivities of these drugs were achieved earlier and the elimination rates were faster than for morphine. Differences in the uptake of these drugs to the brain, as well as differences in time to maximal normalized uptake and rate of disappearance are considered to reflect differences in the lipophilic character between the drugs. Pethidine had the most rapid and extensive uptake followed by heroin, codeine and morphine in order of decreasing lipophilicity.

Animals↗
PubMed1984

Comparison of different clearance estimates for metoprolol in the rhesus monkey.

After oral administration, the fraction of unchanged drug available systemically is predominantly governed by hepatic drug-metabolizing enzyme activity and/or binding to the liver. If the "well stirred" model for hepatic elimination mimics reality, the apparent oral clearance (Clo) of metoprolol, a drug which is completely absorbed and metabolized only by the liver, should reflect the intrinsic clearance (Cli), i.e., the maximum enzyme activity in absence of blood flow limitations. According to theory, the hepatic venous (hv) drug concentrations after an i.v. dose are also a function of Cli. This postulate has previously been verified in the isolated perfused rat liver by others and has now been tested by us in the intact rhesus monkey. We have compared Clo, Cli and the systemic clearance (Cls) of metoprolol in six rhesus monkeys catheterized in the hepatic and femoral veins (hv; fv). They were given simultaneously 37 to 73 micrograms of [3H]metoprolol i.v. and 9 mg of metoprolol per kg b.w. orally. Unlabeled drug was analyzed in plasma by gas chromatography and 3H-labeled metoprolol by liquid scintillation after liquid chromatography separation. The Cls [dose i.v./area under the blood concentration vs. time curve in the femoral vein (AUCs)] varied between 27 and 32 ml X kg-1 X min-1. As expected, the Clo (doseo/AUCs) was considerably higher and ranged from 89 to 147 ml X kg-1 X min-1. The Cli (dosei.v./AUChv) was in the same range as Clo (46-163 ml X kg-1 X min-1). The determined oral availability was 19 to 31% with a mean of 25.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Morphine glucuronidation in the rhesus monkey: a comparative in vivo and in vitro study.

The kinetics of morphine in the rhesus monkey after i.v. or oral administration including the hepatic extraction ratio determined directly in the portal and hepatic veins were compared with the glucuronidation of morphine in liver microsomes from the same animals. The plasma half-lives varied between 102 and 202 min and the apparent volume of distribution was 2.68 to 3.15 l X kg b.wt.-1. The systemic blood clearance (9.2-21.3 ml X min-1 X kg b.wt.-1) was in the same range as the estimated hepatic blood clearance (9.7-23.9 ml X min-1 X kg b.wt.-1). After i.v. administration, the blood concentrations of morphine-3-glucuronide ( M3G ) were 8 to 11 times higher than those of morphine. The molar blood concentration ratio between morphine-6-glucuronide and M3G was 0.04 or less. The ratio between the metabolite levels in blood was similar to the relative formation rates for M3G and morphine-6-glucuronide in liver microsomal preparations (less than .039). The intrinsic hepatic metabolic clearance of morphine as estimated from the apparent enzyme kinetic constants Vmax and Km for the formation of the major M3G metabolite was used to predict the hepatic extraction ratio. The predicted values of the hepatic extraction ratio (0.09-0.14) were, however, underestimates of the experimentally determined hepatic extraction ratio, which varied between 0.61 and 0.74. This indicates that unknown factors in the liver microsomal glucuronidation preclude the use of enzyme kinetics parameters obtained in vitro for the prediction of the hepatic extraction ratio of morphine. For some drugs that are oxidized it has been shown previously that such prediction from in vitro data is possible.

Animals↗
PubMed1983

Biotransformation of benzo[a]pyrene and 7-ethoxyresorufin and heme-staining proteins in microsomes from human fetal liver and placenta.

Microsomal proteins from human fetal livers and mid-gestational and term placentas were stained for heme in an attempt to detect multiple forms of cytochrome P-450. In fetal liver microsomes five protein bands staining for heme in the mol. wt region 46,000-60,000 were found. In the placentas two bands were seen in the region 46,000-52,000. Fetal liver and placental microsomes were assayed for metabolism of benzo[a]pyrene (B[a]P and 7-ethoxyresorufin (7-EOR). The B[a]P metabolites were separated using high performance liquid chromatography. Following incubations with fetal liver microsomes, in general only phenols were detectable, while after incubations with mid-gestational as well as term placentas from smoking women, the 9,10-, 4,5- and 7,8-dihydrodiols were also formed. No quinones were detected. Placental microsomes from non-smoking women did not catalyse the formation of B[a]P metabolites. The 7-EOR O-de-ethylase activity was in the same range (2-5 pmol/min x mg microsomal protein) in the fetal livers as in the mid-gestational placentas. The activities were somewhat higher in the placentas originating from smokers. No correlation between enzymatic activities in vitro and intensity of any specific protein band was observed for the fetal livers of placentas studied.

Benzo(a)pyrene↗
PubMed1983

Steady-state kinetics and analgesic effect of oral morphine in cancer patients.

The steady-state kinetics of morphine given as tablets and solution were compared in 7 cancer patients with chronic pain. There was no accumulation of morphine (20-40 mg) when repeatedly administered every 4 to 6 h. The mean steady-state concentration of morphine during the dose interval varied between 5.9 and 68.4 ng/ml (20.7-240 nmol/l), and was linearly related to the daily dose of morphine. There were no significant differences between the tablets and the solution of morphine with regard to relative oral bioavailability or peak concentration. The time-to-maximum plasma concentrations was significantly longer for the tablets. The pain score profile, assessed by a visual analogue scale during a dose interval, showed a similar pattern after the two oral formulations of morphine. No significant linear relationship between the scores and the plasma concentrations of morphine was observed.

Administration, Oral↗
PubMed1983

Increased oral clearance of metoprolol in pregnancy.

The disposition of oral metoprolol was studied in 5 women during the last trimester of pregnancy and 3 to 5 months after delivery. After a single oral dose of 100 mg the individual peak plasma concentration in the pregnant state was only 20-40% of that after pregnancy. The plasma half-lives of metoprolol were about the same during (average 1.3 h) and after pregnancy (average 1.7 h). By contrast, the area under the plasma concentration versus time curve was much smaller during (mean 262 nmol/1 X h) than after (mean 1298 nmol/1 X h) pregnancy, resulting in an average apparent oral clearance (Clo) of metoprolol that was 4.4 times higher during (362 ml X kg-1 body-weight X min-1) than after pregnancy. The increased Clo in pregnancy is assumed to be due to enhanced hepatic metabolism of the drug. The possible clinical consequence of the difference in the disposition of metoprolol is discussed.

Administration, Oral↗
PubMed1983

Cytosolic epoxide hydrolase in fetal and adult human liver.

The epoxide hydrolase and glutathione S-transferase activity towards styrene oxide as substrate were investigated and compared in fetal and adult human liver cytosols. The rate of formation of styrene glycol from styrene oxide (nmole/min/mg protein) was 0.23 +/- 0.02 (means +/- SE; n = 10) in fetal and 0.83 +/- 0.05 (means +/- SE; n = 14) in adult liver specimens. The enzyme followed Michealis-Menten kinetics in the fetal liver. In adult liver specimens the enzyme showed biphasic kinetics. For comparative purposes, the cytosolic glutathione S-transferase activity was investigated in the cytosolic fractions from the same liver specimens. The fetal activity was 40% of the adult activity 3.9 +/- 0.50 (means +/- SE; n = 10) versus 9.94 +/- 1.75 (means +/- SE; n = 14) nmoles/min/mg protein.

Adult↗
PubMed1983

Morphine metabolism in cancer patients on increasing oral doses--no evidence for autoinduction or dose-dependence.

Four cancer patients with severe chronic pain were treated with oral morphine with increasing doses during 5-8 months. During this period the oral dose was increased 16-23-fold in each of the patients. Morphine, morphine-3- and morphine-6-glucuronide were determined with high performance liquid chromatography in plasma and urine during steady-state, at five or more occasions on different daily doses of morphine. The trough concentrations of morphine and its metabolites were linearly related to the given dose. The relation between the levels of morphine and the two glucuronides was constant in the individual patient and independent of dose and duration of treatment. The average molar ratio between the areas under the plasma concentration-time curves (AUC) for morphine-3-glucuronide and morphine was 34.0 (range 23.0-46.9). The corresponding value for the ratio between morphine-6-glucuronide and morphine was 3.9 (range 2.7-5.6). Our results show that the conjugation of morphine with glucuronic acid is proportional to the dose during long-term treatment with increasing doses, thus this metabolic pathway is not subject to auto-induction, even after very long periods of continuous treatment with high doses.

Aged↗
PubMed1983

Kinetics of clonazepam in relation to electroencephalographic and clinical effects.

The aim of this study was to see if the immediate EEG and clinical response to an intravenous dose of clonazepam was predictive for the effect of oral clonazepam maintenance therapy. Four children with petit mal epilepsy were given clonazepam intravenously during continuous EEG recording. Clonazepam plasma concentrations were determined repeatedly with a high performance liquid chromatographic method using a reversed phase system. The day after the intravenous dose the patients were given oral therapy with clonazepam. Repeated long-term EEG recordings were made and plasma concentrations of clonazepam were determined. There was no clinically satisfactory effect of clonazepam during oral maintenance treatment in three of the children who responded well to the intravenous dose of clonazepam. Thus, the immediate response to intravenous clonazepam was not a good predictor of the long-term effects in our patients.

Adolescent↗
PubMed1983

Epoxide hydrolase in human fetal liver.

Epoxide hydrolase activity towards styrene oxide was measured in the microsomal fraction of 20 human fetal livers. The enzymatic activity was 5.60 +/- 0.52 nmol/min/mg (mean +/- SE) which is about 40% of the previously reported value in human adult liver microsomes. No relation between enzymatic activity and fetal age was observed. The kinetics of the enzyme were studied in 6 different livers and found to obey Michaelis-Menten kinetics. The Km ranged between 0.25 and 0.54 mmol/l and Vmax between 7.2 and 16.7 nmol/min/mg microsomal protein. The enzyme was inhibited both by 1,1,1-trichloropropene-2,3-oxide (TCPO; 0.25 mmol/l) and benzo(a)pyrene-4,5-oxide (BPO; 0.2 mmol/l). Those substances inhibited the epoxide hydrolase by 61 and 14%, respectively, at 1 mmol/l styrene oxide. Thus TCPO was considerably more potent as an inhibitor of the fetal liver styrene oxide hydrolase. Lineweaver-Burk plots of the inhibition data revealed that TCPO exerts an uncompetitive mixed type of inhibition.

Benzopyrenes↗
PubMed1983

Epoxide hydrolase in human placenta at different stages of pregnancy.

The epoxide hydrolase activity towards styrene-7,8-oxide was investigated in the microsomal fraction of 18 human placentas from the midtrimester and the term of pregnancy. The enzymatic activity was 0.40 +/- 0.03 nmol/min/mg microsomal protein. No relation was found between gestational age and the rate of styrene oxide hydration. The kinetics of the enzyme were studied in 3 placentas. Biphasic kinetics were observed in each of the tissue specimens. The enzyme was inhibited both by 1,1,1-trichloropropene-2,3-oxide (0.25 mM) and benzo(a)pyrene-4,5-oxide (0.2 mM) which had similar inhibiting potency.

Animals↗
PubMed1983

Epoxide hydrolase and aryl hydrocarbon hydroxylase in human fetal tissues: activities in nuclear and microsomal fractions and in isolated hepatocytes.

Epoxide formation from drugs, chemicals, food additives and environmental pollutants is catalyzed by cytochrome P-450 dependent monooxygenase(s). Epoxides are converted to glycols or dihydrodiols by epoxide hydrolase (EH). These enzymes are known to be present in the microsomes of different mammalian tissues and in the hepatic nuclei from rats and humans. The balance between the epoxide forming (AHH) and metabolizing (EH) enzyme activities may provide information about the "epoxide exposure" of a tissue. We thus investigated AHH and EH in the nuclear and microsomal fractions from six livers, four kidneys, four lungs, and two adrenals from human fetuses (gestational age between 15 and 24 weeks). Tissues were obtained at legal abortion for sociomedical reasons. AHH activity was measured according to van Cantfort et al (Biochem Biophys Res Commun 79: 505, 1977) using beno (a)pyrene as substrate. EH was measured as described by Jerina et al (Mol Pharmacol 13:342, 1977) using both styrene oxide (SO) and benzo(a)pyrene-4,5-oxide (BPO) as substrate. The nuclear fraction was isolated by a multistep procedure including centrifugation in high density sucrose ( Pacifici et al, unpublished). The hepatic AHH activity (pmole/min/mg; mean +/- SEM) was 11.5 +/- 2.2 in the nuclear fraction and 34.7 +/- 1.7 in the microsomes. In adrenals it was 6.0 (nuclei) and 4.4 (microsomes). The nuclear fraction from kidneys and lungs did not catalyze this reaction at a measurable rate, whereas microsomal AHH activity was 1.3 +/- 0.3 and 5.3 +/- 1.1, respectively, in these tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1983

Styrene oxide metabolism in rhesus monkey liver: enzyme activities in subcellular fractions and in isolated hepatocytes.

The activity and the kinetic behavior of expoxide hydrolase were studied in various subcellular fractions of rhesus monkey liver isolated by differential centrifugation. The purity of the fractions was estimated by morphometric electron microscopy. Hydrolase activity was measured by a specific radiometric assay with [7-3H]styrene oxide as substrate. All isolated subcellular fractions catalyzed the hydration of styrene oxide at a significant rate. With a saturating concentration of substrate (1 mM), the enzymatic activity (nanomole of product per minute per milligram of protein; mean +/- S.E.) turned out to be 1.51 +/- 0.45 (nuclear fraction), 3.50 +/- 1.11 (mitochondrial fraction), 14.8 +/- 2.26 (microsomal fraction) and 1.69 +/- 0.37 (soluble fraction). The hydrolase obeyed Michaelis-Menten kinetics in each fraction. Vmax (nanomole per minute per milligram; mean +/- S.E.) was 1.64 +/- 0.65 (nuclear fraction) 3.87 +/- 1.71 (mitochondrial fraction), 19.8 +/- 5.4 (microsomal fraction) and 2.72 +/- 1.36 (soluble fraction). The Km (millimole; mean +/- S.E.) values in the fractions were 0.09 +/- 0.02, 0.07 +/- 0.01, 0.23 +/- 0.15 and 0.64 +/- 0.40, respectively. The metabolism of styrene oxide was also studied in isolated hepatocytes from rhesus monkey. These cells hydrated the substrate easily whereas the conjugation of styrene oxide with glutathione was not measurable. Our results show that epoxide hydrolase is present in all subcellular fractions of the rhesus monkey liver. Styrene oxide is preferentially metabolized by hydration to styrene glycol in the isolated hepatocytes of this species and no conjugation with glutathione was found under the incubation conditions used.

Animals↗
PubMed1982

Morphine glucuronidation in human fetal and adult liver.

The glucuronyltransferase activity towards morphine was measured in microsomes isolated from liver specimens obtained from human fetuses and cancer patients. All the fetal livers investigated had measurable UDP-glucuronyltransferase activity towards morphine. There was no correlation between the gestational age (15 to 27 weeks) and the glucuronidation rate. The mean value of the enzymatic activities was higher in fetal livers obtained by hysterotomy (0.20 nmoles x min-1 x mg-1) than in livers obtained after induced abortion (0.11 nmoles x min-1 x mg-1). The average rate of glucuronidation in microsomes from adult liver (mean 1.15 nmoles x min-1 x mg-1) was 6 to 10 times higher than in the fetal liver microsomes. Together with previous investigations on human adult and fetal liver glucuronidation, the present results support the theory of heterogeneity of human UDP-glucuronyltransferase.

Adult↗