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PubMed1994

3,5,5-Trimethylhexanoylferrocene induction of heme oxygenase activity in normal hepatocytes.

Recent work showed that the combination of 50 microM glutethimide plus 50 microM ferric nitrilotriacetate (FeNTA) synergistically induces heme oxygenase (HO) activity in cultured chick embryo liver cells (Cable et al., Biochem Biophys Res Commun 168: 176-181, 1990). This synergistic induction is due to increased heme synthesis, which then acts to increase HO gene transcription. The aim of the current studies was to characterize the effects on hepatic heme metabolism of (3,5,5-trimethylhexanoyl)ferrocene (TMH-ferrocene), which causes hepatic iron-loading in rats. Unlike FeNTA, TMH-ferrocene alone maximally induced HO activity at 5-10 microM TMH-ferrocene. At higher concentrations, HO activities declined, as did total cellular protein synthesis. Induction of HO was maximal after a 12-hr exposure to TMH-ferrocene, similar to induction by glutethimide plus FeNTA. The effect of TMH-ferrocene on HO could not be ascribed to greater cellular uptake of iron, since cell-associated iron levels were higher after FeNTA than after TMH-ferrocene treatment. TMH-ferrocene (up to 20 microM) did not induce delta-aminolevulinic acid synthase activity. Uroporphyrin accumulation in cells treated with TMH-ferrocene was minimal, but the combination of TMH-ferrocene and glutethimide caused a synergistic increase in uroporphyrin accumulation, similar to treatment with glutethimide plus FeNTA. 4,6-Dioxoheptanoic acid, an inhibitor of heme synthesis, blocked the induction of HO caused by glutethimide and FeNTA, but did not decrease the induction of HO by TMH-ferrocene. TMH-ferrocene-mediated induction of HO does not appear to be due to lipid peroxidation, since malondialdehyde formation was greater for ferrocene (a structural analog of TMH-ferrocene that does not induce HO) than for TMH-ferrocene. Furthermore, the anti-oxidant, butylated hydroxyanisole, which prevented lipid peroxidation, decreased HO induced by glutethimide plus FeNTA, but butylated hydroxyanisole did not affect HO induced by TMH-ferrocene. We conclude that, unlike the combination of glutethimide plus FeNTA, TMH-ferrocene induces HO activity by a mechanism that is independent of cellular heme synthesis.

Animals↗
PubMed2003

The study of codeine-gluthetimide pharmacokinetic interaction in rats.

A high-performance liquid chromatographic (HPLC) assay with native fluorescence detection was developed for the simultaneous quantification of codeine and its two metabolites, morphine and morphine-3-glucuronide (M-3-G), in rat plasma. Solid-phase extraction was used to separate codeine and its metabolites from plasma constituents. Extraction efficiencies of codeine, morphine and M-3-G from rat plasma samples were 97, 92 and 93%, respectively. The chromatographic separation was performed using a reversed-phase C18 column and an elution gradient at ambient temperature. Using native fluorescence detection (excitation at 245 nm and emission at 345 nm), the detection limits of 50 ng/ml for morphine, 25 ng/ml for codeine and 20 ng/ml for M-3-G were obtained. The method had good precision, accuracy and linearity, and was applied to the study of glutethimide's influence on codeine metabolism in rat, following single doses of codeine-glutethimide association. The results confirmed the fact that glutethimide was responsible for a significant increase of morphine plasma levels and for their maintenance in time, concomitant with a significant decrease of M-3-G plasma levels, explained by the inhibition of morphine glucuronidation. In conclusion, glutethimide potentiates and prolongs the analgesic effect of codeine by a pharmacokinetic mechanism.

Animals↗
PubMed1979

The [14C]-aminopyrine breath test. A comparison of different forms of analysis.

1 Following ingestion of [14C]-aminopyrine, breath 14CO2 data were analysed from normal individuals, patients with hepatic disease, epileptics receiving anticonvulsant therapy and volunteers before and after treatment with glutethimide. 2 The 'standard' 2 h [14C]-aminopyrine breath test discriminated successfully between the main groups but failed to detect the change in microsomal enzyme function produced by glutethimide. 3 A 'modified' form of the 2 h breath test calculated from the area under the breath specific activity curve detected the increase in demethylation following glutethimide. 4 The breath elimination constant (Kb) derived from the breath 14CO2 disappearance curve was as sensitive as the 'modified' 2 h breath test and was simpler to compute. 5 Glutethimide 500 mg/day for 14 days resulted in a 42% increase in the metabolic clearance of antipyrine and a 26% increase in demethylation of [14C]-aminopyrine.

Aminopyrine↗
PubMed1989

Immunochemical detection of different isoenzymes of cytochrome P-450 induced in chick hepatocyte cultures.

This study investigated whether the same cytochrome P-450 (P-450) isoenzymes were inducible in cultures of chick-embryo hepatocytes as in the liver of chicken embryos. We purified two isoenzymes of cytochrome P-450 from the livers of 17-day-old-chick embryos: one of molecular mass approx. 50 kDa induced in vivo by the phenobarbital-like inducer glutethimide, and the second of approx. 57 kDa induced by 3-methylcholanthrene. Rabbit antiserum against the 50 kDa protein inhibited benzphetamine demethylase activity in hepatic microsomes (microsomal fractions) from glutethimide-treated chick embryo. Antiserum to the 57 kDa protein inhibited ethoxyresorufin de-ethylase activity in hepatic microsomes from methylcholanthrene-treated chick embryo. Cultured chick hepatocytes were treated with chemicals known to induce isoenzymes of P-450 in rodent liver. The induced P-450s were quantified spectrophotometrically and characterized by immunoblotting and enzyme assays. From these studies, chemical inducers were classified into three groups: (i) chemicals that induced a P-450 isoenzyme of 50 kDa and increased benzphetamine demethylase activity: glutethimide, phenobarbital, metyrapone, mephenytoin, ethanol, isopentanol, isobutanol, lindane, lysodren; (ii) chemicals that induced a P-450 isoenzyme of 57 kDa and increased ethoxyresorufin de-ethylase activity: 3-methylcholanthrene and 3,3',4,4'-tetrachlorobiphenyl; and (iii) the mono-alpha-substituted 2,3',4,4',5-pentabromobiphenyl, which induced both proteins and both activities. The immunochemical data showed that chick-embryo hepatocytes in culture retain the inducibility of glutethimide- and methylcholanthrene-induced isoenzymes of P-450 that are inducible in the liver of the chicken embryo.

Animals↗
PubMed1964

A CLINICAL EVALUATION OF FOUR HYPNOTIC AGENTS, USING A LATIN-SQUARE DESIGN.

A double-blind study with a Latin-square design was undertaken on 25 elderly patients, using a placebo and four hypnotic drugs: ethchlorvynol 500 mg., glutethimide 500 mg., chloral hydrate 500 mg., and secobarbital sodium 100 mg. The trial lasted for five weeks. The drugs were all effective compared with the placebo, differences in sleeping time being statistically significant. Differences between these four drugs were not statistically significant. Sleep was induced soonest by secobarbital and ethchlorvynol. Ethchlorvynol and glutethimide had a relatively somewhat longer period of activity than the others. Glutethimide produced most side effects, especially morning drowsiness. Ethchlorvynol and chloral hydrate produced relatively few cases of drowsiness.

Aged↗
PubMed1975

Clinical implications of warfarin interactions with five sedatives.

The intensity, uniformity and time course of anticoagulant interference by phenobarbital, secobarbital, glutethimide, chloral hydrate and methaqualone were systematically investigated in 16 patients receiving coumarin therapy. Each subject received an individualized fixed daily dose of warfarin and served as his own pre- and postsedative treatment control. Prothrombin times were measured four times weekly during five long-term experiments. Anticoagulant inhibition was observed during the administration of phenobarbital, secobarbital and glutethimide; there was no significant change in prothrombin test results during the trials of chloral hydrate and methaqualone. Barbiturates and glutethimide should not be administered to patients receiving coumarin drugs. The concurrent use of drugs from these groups is decreasing according to a survey of 200 hospital medical records. Chloral hydrate and methaqualone interact pharmacologically with orally administered anticoagulant agents, but the effect is not clinically significant. It is concluded that chloral hydrate and methaqualone may be administered safely without additional caution in prothrombin test monitoring during oral anticoagulant therapy.

Administration, Oral↗
PubMed1984

The effects of enzyme induction and enzyme inhibition on labetalol pharmacokinetics.

The oral and intravenous pharmacokinetics of labetalol were determined in five subjects before and after a 3 week course of glutethimide 500 mg/day. After glutethimide there was a significant reduction in the AUC after the oral dose of labetalol, from 40,596 +/- 11,534 (mean +/- s.e. mean) to 22,057 +/- 6,276 ng ml-1 min (2P less than 0.05), and systemic bioavailability was reduced from 30.3 +/- 2.8 to 17.0 +/- 3.5% (2P less than 0.001). There was no significant change in labetalol plasma concentration-time curve (AUC) following an intravenous dose, half-life, volume of distribution, and plasma clearance. The oral and intravenous pharmacokinetics of labetalol were determined in six subjects before and after a 3 day course of cimetidine 1.6 g/day. After cimetidine there was a significant reduction in the volume of distribution of labetalol, from 520 +/- 51 to 445 +/- 24 1 (2P less than 0.05). The AUC of labetalol after the oral dose increased by 66%, from 51,029 +/- 7,950 to 84,772 +/- 19,444 ng ml-1 min (2P = 0.06). The systemic bioavailability of labetalol increased from 25.1 +/- 2.4 to 39.0 +/- 7.6% (2P = 0.06). There was no significant change in labetalol AUC after the intravenous dose, half life, and plasma clearance. There were no significant changes in resting heart rate and supine systolic and diastolic blood pressure following labetalol plus glutethimide, or labetalol plus cimetidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

The interaction of cigarette smoking and chronic drug ingestion on human drug metabolism.

1. Drug metabolism was assessed by the disappearance rate of antipyrine as measured in saliva. Results were expressed in terms of both clearance and half life. 2. Basal measurements of antipyrine disappearance rate were performed in seven non-smokers and six smokers. After administration of glutethimide 250 mg daily for 7 days a second measurement of antipyrine disappearance rate was made. 3. Glutethimide enhanced antipyrine metabolism in both smokers and non-smokers. The degree of change in both groups was similar. 4. A similar study was carried out with a smaller dose (125 mg) of glutethimide. There was no significant difference between smokers and non-smokers.5. The data are consistent with smoking and chronic drug ingestion having additive effects on enhancement of hepatic drug metabolism.

Adult↗
PubMed1979

Fixed-bed uncoated charcoal hemoperfusion in the treatment of intoxications: animal and patient studies.

We examined the efficacy of a new, fixed-bed, uncoated charcoal device in experimentally intoxicated dogs and in drug-intoxicated as well as chemically poisoned patients. In the animal studies, 4 h of hemoperfusion resulted in a significant decrease in the blood level of phenobarbital, salicylate, pentobarbital and glutethimide. The drug clearances varied between 97 +/- 10 and 129 +/- 6 ml/min. However, the total amount of drug removed was higher for phenobarbital and salicylate which have a small apparent volume of distribution (AVD) than for pentobarbital and glutethimide which have an AVD greater than total body water. We next treated 14 patients suffering from a wide variety of intoxications. Patients intoxicated with phenobarbital, methsuximide, chlordane and Amanita muscaria all showed a significant improvement in their clinical status. Patients intoxicated with ethchlorvynol, glutethimide, methaqualone, podophyllin and fluoroacetamide did not improve. Charcoal hemoperfusion may be useful in patients poisoned with drugs characterized by an AVD smaller than total body water. No major complications were encountered during the hemoperfusions.

Adolescent↗
PubMed2001

Isolation of regioisomers of N-alkylprotoporphyrin IX from chick embryo liver after treatment with porphyrinogenic xenobiotics.

Several porphyrinogenic xenobiotics cause mechanism-based inactivation of cytochrome P450 (P450) isozymes with concomitant formation of a mixture of four N-alkylprotoporphyrin IX (N-alkylPP) regioisomers, which have ferrochelatase inhibitory properties. To isolate the four regioisomers of N-methylprotoporphyrin IX (N-methylPP), 3,5-diethoxycarbonyl, 1-4-dihydro-2,4,6-trimethylpyridine (DDC) was administered to untreated, beta-naphthoflavone-, phenobarbital-, and glutethimide-pretreated 18-day-old chick embryos. Separation of the N-methylPP regioisomers by high pressure liquid chromatography (HPLC) revealed no marked difference in the regioisomer pattern among the different treatments. After administration of griseofulvin, allylisopropylacetamide (AIA), or 1-[4-(3-acetyl-2,4,6-triemethylphenyl)-2,6-cyclohexanedionyl]-O-ethyl propionaldehyde oxime (ATMP) to untreated and glutethimide-pretreated 18-day-old chick embryos, an N-alkylPP was isolated after AIA administration only. This finding strengthened previous reports of the species specificity of N-alkylPP formation with griseofulvin and ATMP. A series of dihydropyridines, namely 4-ethylDDC, 4-hexylDDC, and 4-isobutylDDC were administered to untreated and glutethimide-pretreated 18-day-old chick embryos and hepatic N-alkylPPs were isolated and separated by HPLC into regioisomers. The regioisomer patterns obtained did not support a previous proposal of masked regions above both rings B and C in the heme moieties of the P450 isozymes responsible for N-alkylPP formation. However, the data support the hypothesis of a partially masked region above ring B alone. The regioisomer patterns were in agreement with results previously obtained in rats showing that the percentage of Nc and (or) ND regioisomers in the regioisomer mixture increases as the length and bulk of the 4-alkyl substituent of a DDC analogue increase. Differences in the regioselectivity of heme N-alkylation may be due to intrinsic chemical features of DDC analogues themselves or to differences in the P450 isozymes inactivated.

Animals↗
PubMed1976

Resin hemoperfusion for acute drug intoxication.

Eight patients with drug intoxication were hemoperfused on ten occasions at a blood-flow rate of 300 ml/min with a 650gm column of Amberlite XAD-4 resin, which is a macroreticular resin with a specific adsorptive attraction for lipid-soluble organic molecules. Column clearances of glutethimide and a variety of barbiturates ranged from 207 to 300 ml/min for treatment sessions extending from 2 1/2 to ten hours. After ingestion of 75 gm of glutethimide, one patient received hemoperfusion on three successive days for nine, ten, and eight hours, respectively. She recovered after the column removed over 30 gm of drug. The patients demonstrated dramatic clinical responses with no evidence of meaningful toxic reactions. Column hemoperfusion with Amberlite XAD-4 resin was simpler and more effective than any known method of removing barbiturates and glutethimide from the blood of patients with drug overdoses.

Adult↗