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Biomedical subjects

D D Breimer

Publications and source records attributed to D D Breimer.

At least 307 records · Page 17Linked to original sources
PubMed1979

Rectal bioavailability of lidocaine in man: partial avoidance of "first-pass" metabolism.

It is often speculated that after rectal administration drugs will enter the systemic circulation without first passing through the liver, because at least the lower hemorrhoidal veins are not connected to the portal system. To test this hypothesis, the systemic availability of the high-clearance drug lidocaine was investigated in 6 healthy subjects following administration of 200 mg intravenous, 300 mg oral, and 300 mg rectal lidocaine in a balanced crossover design. Plasma and whole blood concentrations of lidocaine were measured by capillary gas chromatography. The mean rectal systemic availability was higher than the oral: 63% vs 31% (whole blood) and 71% vs 34% (plasma). The elimination half-lifes (t1/2els) lidocaine were about the same intravenously and orally, whereas these were slightly longer after rectal administration. The oral and rectal investigations were repeated in the same panel of volunteers about 6 mo later. The mean rectal systemic availability, based on plasma concentrations, was then 67% vs 27% orally. Intraindividual variability was rather small, indicating that oral and rectal bioavailability of lidocaine is reproducible in individuals. An equation was derived for the calculation of the fraction of the dose given rectally that bypasses the liver after absorption which is slightly more than half the dose, assuming that dose is 100% absorbed. This investigation indicates that in principle it is possible to avoid, at least partly, drug loss caused by "first-pass" metabolism by giving the drug rectally.

Administration, Oral↗
PubMed1979

Xenobiotica-metabolizing enzymes in Drosophila melanogaster: activities of epoxide hydratase and glutathione S-transferase compared with similar activities in rat liver.

Activities of epoxide hydratase and glutathione (GSH) S-transferase were investigated in subcellular fractions of Drosophila melanogaster, and these activities were compared with analogous enzymic activities in extracts from rat liver. Microsomes of Drosophila were active in the hydratation of styrene oxide catalyzed by epoxide hydratase. The post-microsomal supernatant of Drosophila catalyzed the conjugation of GSH with 1-chloro-2,4-dinitrobenzene. However, GSH S-transferase activity with styrene oxide as the electrophilic substrate was not measurable. The respective specific activities of epoxide hydratase (per mg microsomal protein) and GSH S-transferase (per mg cytosolic protein) were factors of 5- and 10-fold lower than the corresponding activities in rat liver. However, when expressed per gram body weight, activities of both epoxide hydratase and GSH S-transferase were 3 times higher for Drosophila enzymes. The apparent Km values for the two Drosophila enzymes were higher, whereas the apparent Km values were lower, than the values found for the rat-liver enzymes. Among 3 different Drosophila strains (a wild-type, a white eye-color carrying mutant strain and a DDT-resistant strain), preliminary experiments showed no differences as far as these two enzymic activities were concerned. It is concluded that the results obtained in genetic toxicology testing with Drosophila are probably relevant to effects to be expected in mammalian systems with compounds requiring metabolic processes involving the enzymes investigated here.

Animals↗
PubMed1979

Pharmacokinetics and metabolism of various benzodiazepines used as hypnotics.

1 In the management of insomnia with drugs, any action should be restricted to the duration of the night and residual effects should be absent during the day-time. The intermittent type of drug action desired is fundamentally different from drug treatment where a constant effect is sought. 2 Duration of drug action is dependent on the kinetics of distribution and elimination of the parent drug and its effective metabolites. In addition biopharmaceutical factors, such as those which promote a rapid rate of absorption, are important. 3 These considerations serve as a guide for a review of the kinetics and metabolism of various benzodiazepines.

Anti-Anxiety Agents↗
PubMed1979

Pharmacokinetics of pemoline in plasma, saliva and urine following oral administration.

1 Pemoline concentrations were measured in plasma and saliva following a single oral dose (37.5 or 50.0 mg) to healthy volunteers. In addition urinary excretion rates and cumulative urinary excretion of the parent compound and its oxazolidinedione metabolite were determined. 2 The plasma curves exhibited a mean elimination half-live of 11.0 +/- 1.2 h (n=4). Peak levels were reached at 2.7 +/- 0.6 h (n=4). The saliva concentrations were about 50% lower than the corresponding plasma concentrations during the elimination phase. During the absorption phase irregularities in the saliva to plasma concentration ratios were observed. 3 In urine 47.0 +/- 8.4% of the dose (n=6) administered was excreted as unchanged drug and only 3.7 +/- 0.8% (n=3) as the oxazolidinedione metabolite. Urinary half-lives were slightly shorter than the corresponding plasma half-lives.

Administration, Oral↗
PubMed1979

Assay of antipyrine and its primary metabolites in plasma, saliva and urine by high-performance liquid chromatography and some preliminary results in man.

A reversed phase system for the HPLC separation of antipyrine and its primary metabolites is described. Based on this system an assay procedure for antipyrine in plasma and saliva was developed with a lowest measurable concentration of 25 ng/ml and precision of +/- 3.6 and +/- 4.5%, respectively. Furthermore, assays for the parent compound, 3-hydroxymethyl-antipyrine, norantipyrine and 4-hydroxy-antipyrine in urine were developed. The lowest measurable concentration for these compounds is about 100 ng/ml except for 3-hydroxymethyl-antipyrine with a lowest measurable concentration of about 200 ng/ml. The precision was established at +/- 3.6 and +/- 5.0% for 3-hydroxymethyl-antipyrine, and antipyrine, respectively, and +/- 7.0 and +/- 3.6% for norantipyrine and 4-hydroxy-antipyrine, respectively. The method was applied to studies on antipyrine metabolism in humans. Following administration of a single dose of 500 mg antipyrine to 5 healthy volunteers, 3.3 +/- 1.2% of the dose was recovered from 48-hour hydrolyzed urine as unchanged drug, 39.7+/- 8.7% as 3-hydroxymethyl-antipyrine, 14.5 +/- 6.8% as norantipyrine and 28.5 +/- 2.2% as 4-hydroxy-antipyrine.

Animals↗
PubMed1979

Assay of 3-carboxy-antipyrine in urine by capillary gas chromatography with nitrogen selective detection. Some preliminary results in man.

An assay procedure is described for 3-carboxy-antipyrine in urine using gas chromatography with a support coated open tubular capillary column (Carbowax 20M), a solid injection system and nitrogen selective detection. 3-Carboxy-antipyrine was analyzed after derivatization with diazomethane and using 4-bromo-antipyrine as internal standard. Following extraction of the urine samples with a mixture of organic solvents linear calibration curves were obtained in the concentration range of 1--50 microgram/ml. The precision was established as +/- 5.0% (n = 5), and the lowest measurable concentration was 1 microgram/ml at a signal-to-noise ratio of 10:1. Preliminary results in 5 human volunteers showed that after orl administration of 500 mg antipyrine, 3.3 +/- 0.8% of the dose was excreted as 3-carboxy-antipyrine in 52 hours' urine. The compound was excreted completely in the unconjugated form.

Administration, Oral↗
PubMed1979

Studies on the different metabolic pathways of antipyrine in rats: influence of phenobarbital and 3-methylcholanthrene treatment.

1. The amounts of antipyrine and its metabolites excreted in 24 h urine after i.v. injection of 10 mg antipyrine into male Wistar rats were quantified after enzymic hydrolysis with beta-glucuronidase/aryl sulphatase. In 24 h 2.7% of the administered dose was excreted as unchanged antipyrine, 13.3% as 4-hydroxyantipyrine, 7.4% as norantipyrine, 28.9% as 3-hydroxymethylantipyrine and 1.1% as 3-carboxyantipyrine. 2. Treatment with phenobarbital decreased the antipyrine half-life from 65 to 30 min, but did not significantly change the urinary metabolite profile. Only the amount of 3-carboxyantipyrine was significantly different and increased from 1.1 to 2.6% dose. 3. 3-Methylcholanthrene treatment resulted in a decrease of antipyrine half-life from 72 to 37 min. After treatment 4-hydroxyantipyrine was increased from 13.4% to 25.6% dose, whereas 3-hydroxymethylantipyrine was decreased from 26.8% to 8.5% and 3-carboxyantipyrine from 1.3% to 0.2% of the dose respectively; norantipyrine was unchanged. 4. It is concluded that different types of hepatic cytochrome P-450 may be involved in the formation of 4-hydroxyantipyrine on one hand and the formation of 6-hydroxymethylantipyrine on the other. Another possibility is that in methylcholanthrene-treated animals another haemoprotein is formed that results in the formation of more 4-hydroxyantipyrine and less 3-hydroxymethylantipyrine. In any case, the urinary metabolite profile of antipyrine can be used to study changes in the activity of different cytochromes in drug metabolism studies.

Animals↗
PubMed1978

Assay of pemoline in human plasma, saliva and urine by capillary gas chromatography with nitrogen-selective detection.

A simple gas chromatographic assay of the psycho-stimulant pemoline in human urine, plasma and saliva has been developed. Instead of direct extraction of the drug from urine, plasma and saliva, it is hydrolyzed to 5-phenyl-2,4-oxazolidine-dione with 1 N hydrochloric acid. After extraction this compound is methylated with diazomethane and determined by gas-liquid chromatography using a capillary SCOT column with a mixed stationary phase, a solid injection system and a nitrogen-selective detector. 5-Phenyl-2,4-oxazolidinedione, which was also found to be a metabolite of pemoline, could be determined quantitatively in human urine.

Chromatography, Gas↗
PubMed1978

Assay of underivatized intrazepam and clonazepam in plasma by capillary gas chromatography applied to pharmacokinetic and bioavailability studies in humans.

The assay procedure of underivatized, intact nitrazepam and clonazepam in human plasma is described, using gas chromatography with a support-coated open tubular column (OV-17), a solid injection system and electron-capture detection. Clonazepam is used as a internal standard in the assay of nitrazepam and vice versa. Linear calibration curves after a single extraction step were obtained in the concentration range 10--100 ng/ml plasma, with standard deviations less than 4.9%. The sensitivity limit of the method is about 1 ng/ml plasma for both drugs. The method was applied to pharmacokinetic and bioavailability studies of nitrazepam in humans. Seven healthy volunteers received two nitrazepam-containing tablet preparations (5 mg) and plasma concentrations were determined regularly from 15 min to 80 h following drug administration. The mean elimination half-life of nitrazepam was 27 h (range 13-34 h). Considerable intra-individual differences in peak level times between the two preparations were observed, whereas the extent of bioavailability was rather similar.

Adult↗
PubMed1978

Influence of corticosteroid on hexobarbital and tolbutamide disposition.

The influence of 10 days' prednisone treatment on the disposition of hexobarbital and tolbutamide was studied in 7 healthy male volunteers. No significant changes in the pharmacokinetic parameters of the two drugs became apparent, which indicates that prednisone pretreatment does not affect their metabolic activities.

Adult↗
PubMed1977

Gas chromatographic determination of pemoline as 5-phenyl-2,4-oxazolidinedione in human urine.

A simple gas chromatographic assay of the psychostimulant pemoline in human urine has been developed. Instead of extraction of the drug from urine, it is hydrolysed to 5-phenyl-2,4-oxazolidinedione with 1 N hydrochloric acid. After the extraction, this compound is methylated with diazomethane and determined by gas-liquid chromatography using a nitrogen-selective detector and a solid injection system. The method has been applied in preliminary human pharmacokinetic studies, by measuring the urinary excretion rate of pemoline following oral administration. At present, the screening procedures for doping control do not involve the detection of pemoline, but the method described can easily be incorporated in such procedures.

Chromatography, Gas↗
PubMed1977

Stimulation of drug metabolism by rifampicin in patients with cirrhosis or cholestasis measured by increased hexobarbital and tolbutamide clearance.

Eleven patients with hepatic cirrhosis or cholestasis were treated with rifampicin for 7 to 132 days. Ten patients received hexobarbital (7.32 mg/kg) and five received tolbutamide (20 mg/kg) by i.v. infusion prior to and after rifampicin treatment; plasma concentrations of the two test compounds were determined during and after infusion. The average elimination half-life of hexobarbital had decreased from 624 to 262 min and that of tolbutamide from 292 to 160 min following rifampicin treatment. It was calculated that the metabolic clearance of hexobarbital had increased more than two-fold and that of tolbutamide almost two-fold. The results suggests that rifampicin is able to stimulate hepatic drug metabolism in patients with liver disease. It was apparent in general that the induction did not lead to improvement of hepatocellular function during disease as judged by laboratory findings.

Adult↗
PubMed1977

Influence of rifampicin on drug metabolism: differences between hexobarbital and antipyrine.

Six healthy volunteers were treated with 1,200 mg of rifampicin daily for 8 days. Before and immediately afterward each received indocyanine green, hexobarbital, galactose, and antipyrine by intravenous infusion on 3 consecutive days. The plasma concentrations of the drugs were determined several times after infusion. The average elimination half-life of hexobarbital had decreased from 407 to 171 min and its metabolic clearance had increased almost threefold. In contrast, the average elimination half-life of antipyrine was virtually the same on both occasions (6.9 and 7.2 hr) and there was no change in metabolic clearance. In a tuberculous patient treated with rifampicin the antipyrine elimination rate was unaffected. Rifampicin did not influence indocyanine green clearance or galactose elimination capacity. Serum gamma glutamyl transferase was not affected but urinary D-glucaric acid excretion was increased during rifampicin treatment. The experiment with hexobarbital was repeated after 2 weeks in all subjects; half-lives and clearance values had returned to near control values. It appears that rifampicin is a selective inducer of oxidative drug metabolism in man.

Adult↗