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Biomedical subjects

D D Breimer

Publications and source records attributed to D D Breimer.

At least 271 records · Page 15Linked to original sources
PubMed1982

Influence of sex and oral contraceptive steroids on antipyrine metabolite formation.

Our study was undertaken to determine the influence of sex and the use of oral contraceptive steroids on antipyrine clearance and metabolite formation. Our subjects were eight men (M), eight women (F), and eight women who had been using oral contraceptive steroids (OC) for at least 6 mo; all were healthy. The groups were matched for age and smoking and drinking habits. Antipyrine elimination half-life (t1/2) was longer in the OC than in the F group (12.9 +/- 2.0 and 9.7 +/- 1.7 hr) and clearance was lower (2.0 +/- 0.1 and 2.8 +/- 0.5 l/hr), while volume of distribution (Vd) was essentially the same (37.1 +/- 5.7 and 38.5 +/- 4.6 l). The M group had longer t1/2s than the F (11.8 +/- 1.2 and 9.7 +/- 1.7 hr) and greater Vds (47.1 +/- 5.4 and 38.5 +/- 4.6 l), but clearance values were the same (2.8 +/- 0.5 and 2.8 +/- 0.5 l/hr) in the two groups. Compared to the F, the three metabolic pathways of antipyrine appeared to be inhibited in the OC group. Partial clearances for production for the F and OC groups were (l/hr); norantipyrine (NORA) 0.70 +/- 0.13 and 0.42 +/- 0.12, 4-hydroxyantipyrine (OHA) 1.19 +/- 0.37 and 0.83 +/- 0.25, and 3-hydroxymethylantipyrine (HMA) 0.45 +/- 0.10 and 0.33 +/- 0.09. Partial clearance for production in the F group was higher than in the M for OHA (1.19 +/- 0.37 and 0.78 +/- 0.15 l/hr) and NORA (0.07 +/- 0.13 and 0.56 +/- 0.13 l/hr), but not for HMA (0.45 +/- 0.10 and 0.40 +/- 0.05 l/hr). In the F group, total metabolite recovery was higher than the M. We conclude that sex and OC steroids have differential effect on the several metabolic pathways of antipyrine.

Adult↗
PubMed1982

Influence of sex, menstrual cycle and oral contraception on the disposition of nitrazepam.

1 The effects of sex and oral contraceptives (OC) on the disposition of oral nitrazepam were studied in six healthy young males, in six healthy young females in the follicular and luteal phase of the menstrual cycle and in six healthy young females using OC-steroids in two stages of the pill cycle. 2 There was no influence of the menstrual cycle on the pharmacokinetic parameters of nitrazepam, nor was there a significant difference between these parameters in males and females in either phase of the cycle. The elimination half-life was 27.3 +/- 1.3 h in males, 27.7 +/- 1.5 h in females in the follicular phase and 29.6 +/- 1.4 h in the luteal phase of the menstrual cycle. Total plasma clearance was 59.3 +/- 2.7 ml/min, 58.2 +/- 3.3 and 55.8 +/- 5.0 ml/min respectively. 3 The use of OC-steroids did not significantly alter the elimination half-life of nitrazepam: 30.6 +/- 2.3 and 31.2 +/- 2.2 h in the first and second half of the pill cycle. The total nitrazepam clearance in these females (46.6 +/- 4.6 and 45.6 +/- 4.1 ml/min) was significantly lower than in males (P less than 0.05). 4 The protein unbound fraction of nitrazepam was progressively higher going from males (11.4 +/- 0.1%) to females in the luteal phase of the cycle (12.4 +/- 0.5%) to females using OC-steroids (13.5 +/- 0.4%). Only the difference between males and females using OC-steroids was statistically significant. 5 The clearance calculated relative to the unbound drug (intrinsic clearance) was significantly decreased in females taking OC-steroids as compared to males and females not taking them (Cli = 323 +/- 30 ml/min in females using OC-steroids, 530 +/- 37 ml/min in males and 459 +/- 40 ml/min in females). 6 The results of this study are not likely to have important consequences for dosage of nitrazepam as an hypnotic. The most pronounced effect observed was inhibition of nitrazepam clearance and especially intrinsic clearance by OC-steroids. Females on OC-steroids taking a nitrazepam tablet every evening, will have highly steady levels of nitrazepam (and certainly of unbound nitrazepam) than males or females not taking OC-steroids.

Adult↗
PubMed1982

Differential effects of enzyme induction on antipyrine metabolite formation.

1 The influence of enzyme induction with antipyrine and pentobarbitone was studied on the rates of formation of the major metabolites of antipyrine: 4-hydroxyantipyrine, norantipyrine and 3-hydroxymethyl-antipyrine + 3-carboxy-antipyrine. The inducing drugs were given to panels of healthy volunteers for 8 days and prior to and after this period antipyrine total elimination clearance was determined in plasma, whereas the partial clearances for production of the individual metabolites were assessed on the basis of urinary excretion data. 2 Antipyrine total clearance had significantly increased by 16% following treatment with antipyrine, which could almost entirely be attributed to a selective increase in the rate of production of norantipyrine. 3 With pentobarbitone total clearance of antipyrine had increased by 60%, which was associated with a significant increase in the clearance of production of all three metabolites. However, the increase in norantipyrine formation was significantly higher than the increase in 4-hydroxyantipyrine and 3-hydroxymethyl-antipyrine formation. 4 The most likely explanation for these differences in the degree of induction of the different metabolic routes of antipyrine, is that different enzymes are involved in the different routes. Apparently the enzyme involved in norantipyrine formation is most sensitive to induction by antipyrine and pentobarbitone. By measuring rates of antipyrine metabolite formation it may be possible to study the degree of selectivity of enzyme inducers on oxidative drug metabolism.

Adult↗
PubMed1982

3-Hydroxymethyl antipyrine excretion in urine after an oral dose of antipyrine. A reconsideration of previously published data and synthesis of a pure reference substance.

Previously published data from this laboratory on the urinary excretion of 3-hydroxymethyl antipyrine (one of the major metabolites of antipyrine in man) have to be reconsidered, because of use of an impure reference substance in the high-pressure liquid chromatographic assay method. Comparison with newly synthesized, pure 3-hydroxymethyl antipyrine has shown that a correction factor of 0.45 needs to be applied to previously published data. Details of the synthesis of the pure reference 3-hydroxymethyl antipyrine are given.

Administration, Oral↗
PubMed1982

The influence of L-4-oxalysine on carbon tetrachloride-induced changes in drug-metabolizing enzyme activity of mouse liver.

1. Carbon tetrachloride (0.2 ml/kg) and L-4-oxalysine (200 mg/kg per day for two days) were administered to male mice separately, and together, and the liver drug-metabolizing parameters measured. 2. Carbon tetrachloride alone depleted hepatic microsomal protein content by 50% and cytosolic sulphydryl compounds by 90%; oxalysine alone had no effect. 3. Microsomal cytochrome P-450 was decreased by 60%, cytochrome b5 by 30%, ethylmorphine N-demethylation by 50% and 7-ethyoxycoumarin O-deethylation by 80% following carbon tetrachloride administration; oxalysine had no effect on these losses. 4. After administration of carbon tetrachloride, cytosolic glutathione S-transferase activity was decreased by 16%; this effect was not seen when oxalysine and carbon tetrachloride were given together. Oxalysine alone slightly increased this enzyme activity.

Amino Acids, Dicarboxylic↗
PubMed1981

Simultaneous determination of blood concentrations of methohexital and its hydroxy metabolite by gas chromatography and identification of 4'-hydroxymethohexital by combined gas--liquid chromatography--mass spectrometry.

A simple, sensitive and selective method is described for the simultaneous determination of low concentrations (less than 50 ng/ml) of underivatized methohexital and its hydroxy metabolite in small (0.1 ml) samples of human and rat plasma or whole blood by gas chromatography with nitrogen-selective detection. Moreover, the main metabolite in rat and man was identified as 4'-hydroxymethohexital by comparison of chromatograms from gas--liquid chromatography (GLC) with data obtained from GLC--mass spectrometry and 1H-nuclear magnetic resonance spectrometry of this metabolite, produced both by incubating methohexital with isolated rat liver microsomes and by isolating this metabolite from rat urine.

Animals↗
PubMed1981

Hexobarbitone disposition at different stages of intensive care treatment.

The pharmacokinetics of hexobarbitone were investigated in 22 patients in an intensive care unit. The results were compared with those obtained in a healthy group for three time periods: 3rd or 4th day (I), 5-8th days (II) and 13-29th days (III) of treatment. Hexobarbitone 7.32 mg per kg of body weight was administered by i.v. infusion in 60 min. At the end of the infusion, the mean plasma concentration of group I was 71% greater than control group; groups II and III were near to control. In all patients the post-infusion concentration-time course of hexobarbitone could be described by two-compartment kinetics. The biphasic decrease in plasma concentration of hexobarbitone was more rapid in groups II and III, than in either the control group or in group I. At the beginning of treatment patients generally showed an unchanged hexobarbitone half-life, a slightly decreased plasma clearance, a reduction of approximately 50% of the initial distribution volume. (V1) and a reduction of 44% of the distribution volume at steady state. In groups II and III the mean of these values were comparable to control. However, plasma clearance had increased by about 87% in group II compared with control, and after 2-3 weeks (group III) by about 143%. Correspondingly, half-life was reduced by 45% and 58% respectively. The pharmacokinetics were not related to change in liver function. The presence of clinical and bacteriological signs of septicaemia was closely associated with an enhanced hexobarbitone clearance.

Adult↗
PubMed1981

Glutathione S-transferase activity in human fetal and adult tissues.

Quantitative estimations of glutathione S-transferase activities with 1-chloro-2,4-dinitrobenzene as the electrophilic second substrate, in 142 postmortem human tissue specimens derived from 34 different organs of one or more of 13 individuals belonging to various age groups, are presented. Collectively the data indicate: (1) all tissues examined have appreciable levels of enzyme activity; (2) liver, kidney, lung, muscle, heart, adrenal glands, pancreas, and stomach of fetal origin possess higher enzyme activities than those of the adults, and (3) there are wide interindividual variations in the tissue enzyme activities.

Adult↗
PubMed1981

Influence of the genetically controlled deficiency in debrisoquine hydroxylation on antipyrine metabolite formation.

The influence of the genetically controlled deficiency in debrisoquine hydroxylation on antipyrine metabolite formation was studied by giving 500 mg antipyrine to 14 extensive and 10 poor metabolizers of debrisoquine. The pharmacokinetics of antipyrine were determined on the basis of the saliva concentration time curve and the cumulative urinary excretion of 4-hydroxyantipyrine, norantipyrine, 3-hydroxymethyl-antipyrine, and 3-carboxyantipyrine was measured for 32 h following drug administration. Antipyrine elimination half-life, volume of distribution, and total clearance were almost equal for the two groups. Significant differences in the excretion of antipyrine metabolites were not observed, except for 3-hydroxymethyl-antipyrine which was excreted in poor metabolizers about 30% less than in extensive metabolizers (p less than 0.01). However, this difference only reached borderline significance (p less than 0.1) when clearance values for production of this metabolite were calculated. It is concluded that different species of the drug-oxidizing enzymes (cytochrome P-450 system) are involved in the metabolism of debrisoquine and antipyrine. Possibly the enzyme responsible for hydroxylating debrisoquine is partly involved in the formation of 3-hydroxymethyl-antipyrine.

Aging↗
PubMed1981

Differences in inducibility of particulate and cytosolic rat liver glutathione S-transferase activities.

1. Rat liver mitochondrial microsomal glutathione (GSH) S-transferase activities with 1-chloro-2,4-dinitrobenzene as substrate were 11.0 and 11.6%, and with 1,2-dichloro-4-nitrobenzene as substrate were 27.7 and 15.4%, of the corresponding cytosolic activities respectively. 2. Marked difference in inducibility of cytosolic and particulate GSH S-transferase activities were seen after pretreatment of animals with enzyme-inducing agents. 3-Methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin enhanced cytosolic GSH S-transferase activity only. Phenobarbital induced the cytosolic and microsomal enzymes only.

Animals↗