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Biomedical subjects

D D Breimer

Publications and source records attributed to D D Breimer.

At least 235 records · Page 13Linked to original sources
PubMed1984

Influence of rifampicin treatment on antipyrine clearance and metabolite formation in patients with tuberculosis.

The influence of an 8-day therapy with rifampicin (600 mg daily) was studied on antipyrine plasma clearance and metabolite formation in seven patients with tuberculosis (age 18-79 years), who were also treated with isoniazid and pyrazinamide. After rifampicin treatment the elimination half-life of antipyrine had decreased in all patients from 12.9 +/- 5.0 to 8.8 +/- 2.0 h (P less than 0.05). Antipyrine clearance had increased from 2.2 +/- 0.9 to 2.9 +/- 0.7 l/h (P less than 0.05), while no change in apparent volume of distribution was observed. The increase in antipyrine clearance was primarily due to a selective increase in the rate of formation of norantipyrine by 80% from 6.9 +/- 3.4 to 12.4 +/- 3.4 ml/min. Rifampicin seems to induce preferentially the cytochrome P-450 (iso-) enzyme(s) involved in the demethylation of antipyrine to norantipyrine. Other pathways of antipyrine metabolism were hardly affected. This provides further evidence for the involvement of different iso-enzymes of the cytochrome P-450 system in antipyrine metabolism in man.

Adolescent↗
PubMed1984

Antipyrine clearance and metabolite formation in patients with alcoholic cirrhosis.

The effect of liver cirrhosis on plasma clearance and metabolite profile of i.v. administered antipyrine was studied in 23 patients with alcoholic liver cirrhosis (age 37-70 years) and 17 healthy subjects (age 28-55 years). Liver volume was also measured and was found to be larger in patients than in controls, mean values being 1.86 and 1.36 l respectively. The elimination half-life of antipyrine in patients with alcoholic liver cirrhosis was significantly longer than in the healthy subjects (P less than 0.001). Mean values were 39.9 and 10.1 h respectively. Alcoholic liver cirrhosis had no effect on the apparent volume of distribution of antipyrine, but antipyrine plasma clearance was substantially reduced in the patients. Mean clearance values (ranges) were 13.5 (9.3-22.8) ml/min in the patients and 49.3 (31.1-103) ml/min in healthy subjects. Normalization of antipyrine plasma clearance for liver volume resulted in an only slightly increased distinction between patients and healthy subjects, mean values (ranges) being 7.8 (3.3-13.0) ml min(-1) 1(-1) and 36.1 (21.9-35.9) ml min(-1) 1(-1) respectively. The cumulative renal excretion of 4-hydroxyantipyrine (OHA) and norantipyrine (NORA) was significantly lower in patients with alcoholic liver cirrhosis than in healthy subjects, as was the total recovery of antipyrine and major metabolites from urine. Mean values were 15.0, 8.4 and 41.2% of dose in the patients respectively and 24.3, 25.8 and 68.9% of dose in the control subjects. Excreted amounts of total and unconjugated 3-hydroxymethylantipyrine (HMA) and of unchanged antipyrine were the same in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Correlation between the in vivo metabolism of hexobarbital and antipyrine in rats with a portacaval shunt.

To investigate how hepatic malfunction affects the disposition of hexobarbital (HB), an intermediate 'high-clearance' compound, and antipyrine (AP), a low-clearance compound, as well as the correlation between the rates of elimination of these drugs, their pharmacokinetics, were studied in control rats (n = 8) and in rats with a portacaval shunt (PCS; n = 9). Blood concentrations of parent drugs were measured, and urinary excretion of the following metabolites was determined: 3-hydroxymethylantipyrine (HMA), 4-hydroxyantipyrine and norantipyrine as primary metabolites of AP, and 3'-hydroxyhexobarbital (OH-HB) and 3'-ketohexobarbital (K-HB) as primary metabolites of HB. Blood elimination half-lives of AP and HB were more than four times longer in PCS rats than in control rats, increasing from 63.7 +/- 3.9 to 291 +/- 66 min, and from 20.1 +/- 1.8 to 84.2 +/- 7.6 min, respectively. Intrinsic clearance of HB (CLint, HB) was 167 +/- 19 ml/min/kg in controls and 27 +/- 4 ml/min/kg in PCS rats (CLpcs, HB). Intrinsic clearance of AP (CLint, AP) in control rats was 15.1 +/- 0.7 ml/min/kg and 5.9 +/- 0.7 ml/min/kg in PCS rats (CLpcs, AP). PCS reduced clearance for production of metabolites (CLMn) of AP by 50%, but CLMn of HB metabolites was decreased by more than 80%. The CLint, AP, CLint, HB CLpcs, HB, CLpcs, AP, and CLMn data were correlated. Total clearance correlated better in PCS rats than in control rats: r = 0.77 versus r = 0.10, respectively, thus suggesting a decrease in substrate selectivity under pathological conditions. CLOH-HB+K-HB, reflecting the major metabolic pathway of HB, correlated most closely with CLHMA in PCS (r = 0.91). Therefore, the underlying metabolic conversions of HB and AP may be mediated by the same or very similar forms of cytochrome P-450. Our results suggest that the predictive value of the model substrate approach is valid under pathological conditions.

Animals↗
PubMed1984

Pharmacokinetics of benzodiazepines: metabolic pathways and plasma level profiles.

Large differences exist among the various benzodiazepines with regard to their pharmacokinetic properties and metabolism in man. Some are eliminated from the body at a relatively slow rate, e.g. desmethyldiazepam, and others are metabolized rapidly, e.g. midazolam, triazolam. Several benzodiazepines have major active metabolites that are slowly eliminated, e.g. medazepam, halazepam , quazepam and, consequently, should be considered as potentially long-acting. Such differences may be very important clinically because pharmacokinetic data will help to optimize drug therapy with respect to the choice of the proper drug and drug preparation, as well as with the choice of a proper dose and dosage regimen. The therapeutic objectives of drug therapy differ quite considerably for the various clinical indications of benzodiazepines. In anti-anxiety and anti-epileptic therapy, prolonged or continuous treatment is pursued, so that compounds with relatively long or intermediate elimination half-lives of parent drug or active metabolites are of advantage. In hypnotic treatment, on the other hand, the duration of drug action should be restricted to the duration of the night, hence a compound with a short elimination half-life may be preferred. An overview is given of the pharmacokinetics of the major benzodiazepines currently available and of some interesting new ones that are still in the development stage.

Adolescent↗
PubMed1984

Influence of mild thyroid dysfunction on antipyrine clearance and metabolite formation in man.

The salivary kinetics and rates of metabolite formation of antipyrine were studied in 6 hyperthyroid and 6 hypothyroid out-patients on 2 occasions, on admission and when T3 and T4 levels had returned to normal after treatment with carbimazole (hyperthyroidism) or l-thyroxine (hyperthyroidism). In hyperthyroidism the half-life of antipyrine was significantly shorter (p less than 0.05) than after recovery (9.3 +/- 1.0 versus 10.6 +/- 0.9 h). Hypothyroid patients showed a significantly longer elimination half-life before treatment than after recovery (12.7 +/- 2.6 versus 10.3 +/- 2.6 h). Antipyrine clearance in hyperthyroid patients was decreased after treatment from 2.7 +/- 0.3 to 2.4 +/- 0.3 l/h, and it was increased in hypothyroid patients from 2.1 +/- 0.4 to 2.5 +/- 0.5 l/h (p less than 0.05). The changes in clearances for the production of the antipyrine metabolites 4-hydroxyantipyrine (OHA), norantipyrine (NORA) and 3-hydroxymethylantipyrine (HMA) were of the same order of magnitude as total antipyrine clearance, and no selectivity towards any of the metabolic pathways of antipyrine was apparent. Mild thyroid dysfunction seems to affect oxidative drug metabolizing enzyme activity in a non-selective manner and only to a small extent (10-30%). It is suggested that adjustment of the therapeutic regimens of various drugs in mild thyroid disease will only rarely by required on the basis of pharmacokinetic considerations.

Adult↗
PubMed1984

Rectal, oral and I.A. administration of etomidate to rats: significant avoidance of hepatic first-pass elimination following rectal administration.

The systemic availabilities of the hepatic high-clearance drug etomidate following oral and rectal administration to rats were determined. The mean curve following intra-arterial administration to another group of rats was taken as a reference. The results showed that the mean rectal systemic availabilities calculated according to the AUC method and the deconvolution method were considerably higher (70.1% and 67.6% respectively) as compared to the mean values following oral administration (4.5% and 9.2% respectively). The deconvolution method gave detailed information about the profiles of the rate and cumulative amount of drug absorbed versus time. It showed that the mean maximal rate of absorption was higher and the time at which this occurred was shorter after rectal (5343 micrograms/hr and 0.13 hr) than after oral (600 micrograms/hr and 0.23 hr) administration. Mean blood elimination half-lives following rectal administration (112.6 min) were longer than that after i.a. administration (61.7 min). The mean half-life of 22.8 min after oral administration should be considered as a distribution half-life. The mean clearance following i.a. administration was 35.2 ml/min (142.7 ml/min/kg), which is higher than hepatic bloodflow and indicates extra-hepatic metabolism. It is concluded that there is a substantial avoidance of hepatic first-pass elimination of etomidate following rectal administration to rats.

Administration, Oral↗
PubMed1983

Assay of midazolam and brotizolam in plasma by a gas chromatographic and a radioreceptor technique.

A gas chromatographic method (GLC) using a capillary column, electron capture (EC) detection and a solid injection system for the determination of midazolam and brotizolam in plasma is described. Furthermore, the application of a radioreceptor technique (RRA), using a dry and stable benzodiazepine receptor preparation and 3H-flunitrazepam as a labelled ligand for the assay of both drugs is presented. A comparison was made between the RRA and the GLC method. For the gas chromatographic method, linear calibration graphs (r greater than 0.995) was obtained in the range of 0.1 -0.5 ng of brotizalam, and 1.0-5.0 ng of midazolam. Differences between duplicates were less than 8%. The relative affinity of the 1-hydroxymethyl and 4-hydroxy metabolites of brotizolam and midazolam were 0.33 and 0.14 respectively for brotizolam and 0.64 and 0.23 for midazolam. Extraction yields of parents drugs and metabolites were similar. Application of the methods to pharmacokinetic studies of the drugs indicated that they were sufficiently sensitive to measure plasma concentrations for at least three times the elimination half-lives. There was a good correlation between results obtained with the gas chromatographic method and those obtained with the receptor technique. Correlation coefficients were 0.94 (based on 37 samples) for brotizolam and 0.99 (based on on 33 samples) for midazolam, and there were no significant differences between pharmacokinetic parameters obtained with the two methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Azepines↗
PubMed1983

Automated high-performance liquid chromatographic determination of antipyrine and its main metabolites in plasma, saliva and urine, including 4,4'-dihydroxyantipyrine.

A rapid, selective and sensitive method was developed for the determination of antipyrine and its main metabolites in plasma, saliva and urine by an automated high-performance liquid chromatographic system. Using a MOS-Hypersil reversed-phase column with a phosphate buffer--acetonitrile mobile phase, baseline separation of antipyrine, its metabolites 3-hydroxymethylantipyrine, norantipyrine and 4-hydroxyantipyrine, and the internal standard, phenacetin, was achieved within 6 min. Factors regarding the accuracy and precision of the method and the stability of phase I metabolites during sample preparation are discussed, taking into account certain drawbacks of previously published methods. Based on the same chromatographic system a method was developed for the assay of 4,4'-dihydroxyantipyrine in urine. This compound is an important metabolite of antipyrine in the rat, representing 12.6 +/- 1.8% of the administered dose (n = 18).

Animals↗
PubMed1983

Determination of glutathione in biological material by high pressure liquid chromatography.

A rapid and selective determination of reduced glutathione in biological material is described, based on its conjugation with 1-chloro-2,4-dinitrobenzene. The reaction product has a UV absorption maximum at 340 nm and is analysed by reversed phase high pressure liquid chromatography. Linear calibration graphs were obtained in the concentration range between 50 microM and 2 mM glutathione in standard solutions and in biological material (rat liver and bacterial homogenates). The detection limit is about 2 microM glutathione when using 20 microliters injection samples.

Acetylcysteine↗
PubMed1983

Kinetics of five benzodiazepine hypnotics in healthy subjects.

Kinetics of five benzodiazepine hypnotics (15 mg flurazepam, 1 mg flunitrazepam, 5 mg nitrazepam, 10 mg temazepam, and 0.5 mg triazolam) were compared in the same group of 12 healthy subjects. Plasma concentrations of parent drugs were determined by capillary gas chromatography with electron-capture detection. For flurazepam, the N-desalkyl metabolite (DAF) was measured. Flunitrazepam, nitrazepam, temazepam, and triazolam were rapidly absorbed, although there was considerable variability; mean peak times (ranges) were: 1.3 (0.3 to 3) hr, 1.8 (0.7 to 6) hr, 1.2 (0.3 to 4) hr, and 1.1 (0.7 to 2) hr. Plasma concentrations of DAF increased rather slowly and reached their maximum between 3 and 48 hr after flurazepam. There were considerable differences in elimination t1/2s, with means of 35 (15 to 66) hr for flunitrazepam, 28 (22 to 33) hr for nitrazepam, 12 (8 to 22) hr for temazepam, 2.4 (1.4 to 3.9) hr for triazolam, and 84 (40 to 114) hr for DAF. Sex differences in elimination t1/2 were only observed for DAF: 99 hr in women and 69 hr in men. Our results show that there are considerable differences in the kinetics of the diazepines.

Adult↗
PubMed1983

Impairment of phenytoin parahydroxylation as a cause of severe intoxication.

A case history is presented of a patient who developed a severe phenytoin intoxication on a "therapeutic" dose of 300 mg/day. This phenomenon could be ascribed to a poor oxidative metabolizing capacity of this patient for phenytoin, as demonstrated by a low para-hydroxyphenyl-phenylhydantoin to phenytoin ratio in the urine. To characterize the specificity of this metabolic defect, debrisoquine and antipyrine oxidation were also studied. Contrary to expectations, this patient was shown to be an extensive debrisoquine metabolizer; the antipyrine clearance was even higher than normal. These findings suggest that phenytoin para-hydroxylation is regulated by an oxidative enzyme complex different from those which oxidize debrisoquine and antipyrine.

Aged↗
PubMed1983

Disposition of hexobarbitone in healthy man: kinetics of parent drug and metabolites following oral administration.

1 Hexobarbitone plasma kinetics were determined in six healthy volunteers, who received 500 mg hexobarbitone orally. In addition urinary excretion rate and cumulative excretion were measured of its three major metabolites: 3'-hydroxyhexobarbitone, 3'-ketohexobarbitone and 1,5-dimethylbarbituric acid. 2 The mean plasma elimination half-life of hexobarbitone was 3.7 +/- 0.9 h (n = 6). Assuming complete absorption, the volume of distribution and the metabolic clearance were 81.3 +/- 20.5 1 and 16.4 +/- 2.9 1/h, respectively. The mean maximal plasma concentration was 7.1 +/- 2.1 micrograms/ml and was reached 1.2 +/- 0.4 h after drug administration. 3 3'-Hydroxyhexobarbitone and 3'-ketohexobarbitone, which are products of allylic side-chain oxidation of hexobarbitone, were excreted in 24 h to the extent of 4.7 +/- 1.3 and 32.1 +/- 11.9% of the dose, respectively. In the same period, 1,5-dimethylbarbituric acid, which is the end product of the epoxide-diol pathway, was excreted to 18.0 +/- 7.8% of the dose. The ratio of the sum of 3'-hydroxy- and 3'-ketohexobarbitone vs 1,5-dimethylbarbituric acid excreted varied with time and amounted ultimately in 24 h urine to 2.3 +/- 1.0. 4 The half-lives of 3'-hydroxyhexobarbitone and 1,5-dimethylbarbituric acid, calculated from their renal excretion rate curves, amounted 5.2 +/- 0.9 and 6.6 +/- 1.3 h and were significantly longer than the half-life of hexobarbitone in plasma. The half-life of 3'-ketohexobarbitone was 4.2 +/- 0.8 h. The maximum excretion rate of 1,5-dimethylbarbituric acid was reached at 7.7 +/- 1.0 h after administration of hexobarbitone. 3'-Hydroxy- and 3'-ketohexobarbitone were excreted with a maximal rate at 2.2 +/- 0.8 and 2.8 +/- 0.4 h respectively.

Administration, Oral↗
PubMed1983

Pharmacokinetics of brotizolam in healthy subjects following intravenous and oral administration.

Pharmacokinetics and bioavailability of brotizolam after i.v. and oral administration were studied in healthy young volunteers. Kinetic parameters after i.v. administration were: volume of distribution 0.66 +/- 0.19 1/kg, total plasma clearance 113 +/- 28 ml/min, distribution half-life 11 +/- 6 min, and elimination half-life 4.8 +/- 1.4 h (mean values +/- s.d.). Kinetic parameters after oral administration were: absorption lag-time 8 +/- 12 min, absorption half-life 10 +/- 11 min, and elimination half-life 5.1 +/- 1.2 h (mean values +/- s.d.). Bioavailability of brotizolam was 70 +/- 22% when calculated by comparing oral and intravenous area-under-curve values, corrected for intra-individual half-life differences. An alternative calculation method, which is relatively independent of large clearance variations, provided a bioavailability of 70 +/- 24% (range: 47-117%).

Administration, Oral↗
PubMed1983

Comparative pharmacokinetics of brotizolam and triazolam in healthy subjects.

Pharmacokinetics of oral brotizolam (0.50 mg) and triazolam (0.50 mg) were studied in healthy young volunteers. The plasma concentration profile of brotizolam can be described as a one compartmental open model with first-order absorption. The absorption of triazolam was less regular and in half of the subjects was not consistent with first-order kinetics. Inter-individual variability in absorption rate (peak times) was larger for brotizolam. Mean peak times were 1.1 +/- 1.0 h for brotizolam and 1.2 +/- 0.5 h for triazolam. Mean peak concentrations were 7.3 +/- 3.1 ng/ml and 5.0 +/- 3.9 ng/ml respectively. The elimination half-life of brotizolam was twice that of triazolam with mean values of 5.0 +/- 1.1 h and 2.6 +/- 0.7 h respectively. There was no correlation between the half-lives of the two drugs. Protein unbound fraction was similar for triazolam and brotizolam with mean values of 9.9 +/- 1.5% and 8.4 +/- 0.7% respectively.

Administration, Oral↗
PubMed1983

Pharmacokinetics of brotizolam in the elderly.

Disposition of brotizolam in patients aged 71-93 years was compared with that of healthy young subjects aged 21-26 years. The mean elimination half-life of brotizolam was about twice as long in the elderly as in the young subjects: 9.3 (4.0-19.5) h and 4.8 (3.1-6.3) h respectively. Increase in elimination half-life was attributable to a decrease in hepatic clearance, i.e. 40 (20-58) ml/min in the elderly and 109 (77-156) ml/min in the young. Volume of distribution and protein binding were the same with mean values of 0.56 (0.45-0.72) l/kg and 9.0 (6.8-11.9) % in the elderly and 0.63 (0.40-0.77) l/kg and 8.4 (7.5-9.4) % in the young. Absorption rate of brotizolam was relatively slow in the elderly with a mean peak time of 1.7 h compared with 1.1 h in the young. Mean bioavailability was almost 70% for both groups. Normalized for body weight and dose (0.25 mg) mean peak concentrations were 247 (137-395) ng ml-1 kg in the young and 343 (251-446) ng ml-1 kg in the elderly. It is unlikely that substantial drug accumulation will occur if elderly patients ingest 0.25 mg brotizolam nightly.

Administration, Oral↗