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Biomedical subjects

D D Breimer

Publications and source records attributed to D D Breimer.

At least 253 records · Page 14Linked to original sources
PubMed1983

Pharmacokinetics of oral brotizolam in patients with liver cirrhosis.

Disposition of oral brotizolam (0.5 mg) was studied in male patients with liver cirrhosis (patients) and in other patients (control) matched for age, weight, smoking and drinking habits. Absorption of brotizolam was relatively rapid in both groups with a median peak time (range) of 1.0 (0.5-2.0) h. Peak concentrations were also similar with median values of 7.1 (3.2-10.7) ng/ml in patients and 9.4 (2.9-19.0 ng/ml) in controls. Elimination half-life was longer in patients than in controls. The median values were 12.8 (9.4-25) h and 6.9 (4.4-8.4) h respectively (P less than 0.01). In two patients hardly any drug elimination was observed, indicating severe impairment of drug metabolizing activity. The prolongation of the elimination half-life was likely to be due to a decrease in clearance (45 ml/min in patients compared with 64 ml/min in controls), and an increase in volume of distribution (0.62 l/kg and 0.39 l/kg respectively). Median values of protein unbound fraction of brotizolam were 9.2 (7.8-10.4) % in controls and 12.4 (10.4-18.9) % in patients. Clearance of unbound drug was 612 ml/min and 380 ml/min respectively.

Administration, Oral↗
PubMed1983

Influence of 9-hydroxyellipticine and 3-methylcholanthrene treatment on antipyrine metabolite formation in rats in vivo.

The influence of pretreatment of rats with 9-hydroxyellipticine and 3-methylcholanthrene on different enzymes of the hepatic mixed-function oxidase system were studied using antipyrine as model compound. Antipyrine half-lives and clearances were estimated in blood, and the metabolite profile was determined in urine. 3-Methylcholanthrene treatment resulted in an increase in antipyrine clearance from 17 to 75 ml/min per kg. Partial clearance of formation of 4-hydroxyantipyrine was selectively increased from 3.9 to 28.2 ml/min kg, whereas clearance of 3-hydroxymethylantipyrine was decreased from 3.2 to 1.2 ml/min per kg. Norantipyrine formation was increased from 2.7 to 7.2 ml/min per kg, while 4,4'-dihydroxyantipyrine formation was unchanged. 9-Hydroxyellipticine treatment resulted in no change in the total clearance, and only the clearance of 4,4'-dihydroxyantipyrine was decreased, from 2.5 to 1.5 ml/min per kg. After pretreatment with 3-methylcholanthrene, 9-hydroxyellipticine treatment resulted in a selective decrease in the clearances of 4-hydroxyantipyrine, from 28.2 to 15.8 ml/min per kg, and of 4,4'-hydroxyantipyrine, from 3.8 to 1.6 ml/min per kg. From these results it is concluded, that 9-hydroxyellipticine is a selective inhibitor of the activity of some of the cytochrome P-450s involved in antipyrine metabolism, though this inhibition does not effect all of these enzymes, nor is it restricted to polycyclic hydrocarbon-induced activity. These results further substantiate the value of antipyrine as a model substrate, for they indicate that the formation of all four metabolites of antipyrine in rats is mediated by different (iso-)enzymes.

Alkaloids↗
PubMed1983

Influence of allylisopropylacetamide and phenobarbital treatment on in vivo antipyrine metabolite formation in rats.

The influence of pretreatment with allylisopropylacetamide (AIA) and phenobarbital (PB) on the pharmacokinetics and metabolite profile of antipyrine was studied in rats in vivo. Antipyrine concentrations were measured in blood and urine, and four metabolites (4-hydroxyantipyrine, norantipyrine, 3-hydroxymethylantipyrine and 4,4'-dihydroxyantipyrine) were determined in urine. Treatment with PB increased antipyrine blood clearance from 11.1 to 59.1 ml/min per kg. The clearances for production of metabolites all increased between four- and five-fold, indicating non-selective induction. Treatment with AIA resulted in a reduction of antipyrine clearance to 5.6 ml/min per kg. The clearances to all four metabolites were decreased to about the same extent (52-65% of control values) indicating non-selective inhibition. Treatment with AIA after PB treatment strongly inhibited drug-metabolizing enzyme activity. Blood clearance of antipyrine was reduced from 59.1 to 12.3 ml/min per kg. Clearances to the metabolites were again inhibited non-selectively (to 20-28% of PB-induced values). In contrast to previous reports, AIA in this study inhibited non-induced oxidative microsomal enzyme activity. This inhibition closely resembled AIA inhibition of PB-induced cytochromes. Therefore it is concluded that in untreated rats antipyrine is predominantly metabolized by PB-types of cytochrome P-450.

Acetamides↗
PubMed1983

Pharmacokinetics of simultaneously administered hexobarbital and heptabarbital in rats: an alternative approach to metabolic correlation studies.

The pharmacokinetics of hexobarbital and heptabarbital were studied after simultaneous oral administration to rats in order to correlate their rates of metabolism. Hexobarbital and heptabarbital were chosen for this purpose as model substrates because of their structural, pharmacokinetic as well as metabolic similarity. Blood concentrations were measured for 2 hr after administration by a capillary gas chromatographic method. In control rats (n = 8) elimination half-lives and intrinsic clearance values ranged between 13 to 28 min and 96 to 435 ml/min X kg for hexobarbital and between 8 to 21 min and 84 to 371 ml/min X kg for heptabarbital, respectively. A short-term pretreatment of rats (n = 7) with phenobarbital resulted in small but significant increases in the rates of metabolism of both barbiturates, whereas treatment of rats with 3-methylcholanthrene (n = 5) resulted in a reversed effect. Correlation of the elimination half-lives of the two drugs in all experiments was only weak (r = 0.70). The intrinsic clearance values reflecting enzyme activity in vivo, however, were found to correlate very strongly (r = 0.97). The results of this study suggest that an experimental approach, in which intraindividual differences are eliminated, appropriate kinetic parameters are studied and similarity of metabolic profiles are taken into consideration are preferable to the previously applied longitudinally designed correlation studies.

Animals↗
PubMed1983

Variability in human drug metabolism and its implications.

Apart from the well known factors involved in drug absorption, distribution and renal excretion, the major cause for interindividual differences in the kinetics of drugs in man is the variability in drug metabolizing activity. A critical review of the influence of genetic factors, age, sex, smoking, alcohol, diet, liver disease and thyroid disease is undertaken. Additionally, drugs causing microsomal induction or inhibition and the effect of exposure to chemicals must be known at a relatively early stage in new drug development. "First-pass" hepatic effect and enzyme saturation are respectively responsible for the wide range of plasma concentrations of some highly liver-extracted drugs or for non-linear kinetics. The implications of variability in human drug metabolism are discussed for drug therapy in daily practice and for new drugs under development. It can be concluded that a high degree of interrelationships between genetic and environmental factors exists in the case of most drugs and that many drugs require dose individualization during actual therapy.

Aging↗
PubMed1983

Correlation between the in vivo metabolism of hexobarbital and antipyrine in rats.

Two model substrates for oxidative hepatic enzyme activity, viz. hexobarbital (HB) and antipyrine (AP), were given simultaneously to rats by the oral route of administration. Blood concentrations of HB and AP were measured simultaneously by a gas chromatographic method and the urinary excretion of six metabolites arising from AP and HB also was determined; norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine (HMA) by high-performance liquid chromatography; 3'-hydroxyhexobarbital, 3'-ketohexobarbital and 1,5-dimethylbarbituric acid by gas-liquid chromatography. The apparent intrinsic clearances of HB (CL*int,HB) and AP (CL*int,AP) and the clearance for production of the various metabolites were correlated in an attempt to establish whether HB and AP have metabolic pathways mediated by the same or very similar forms of cytochrome P-450. In order to create broadly ranging and evenly distributed clearance values, 3-methylcholanthrene (3-MC)- and phenobarbital (PB) pretreated rats were employed in conjunction with a control group of untreated animals. CL*int,HB and CL*int,AP were both increased by PB pretreatment, but 3-MC-pretreatment increased CL*int,AP, whereas CL*int,HB was decreased. CL*int,HB and CL*int,AP were found to correlate poorly, when all groups were taken into consideration (r = -0.08). The formation of AP-metabolites was inducible by both PB and 3-MC, and good correlations between rates of formation of AP-metabolites and CL*int,HB and CL3'-hydroxy-HB + 3'-keto-HB were obtained.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Factors affecting the error in the Loo-Riegelman method for estimating the rate of drug absorption. Some suggestions for a practical sampling schedule.

During the development of a new computer program for the Loo-Riegelman method for the estimation of the rate drug absorption, it was found that many factors can affect the accuracy of the estimated absorption rate constant (ka). In this paper a survey of the factors affecting the errors in the estimation of ka by the Loo-Riegelman method is made. By simulating data and computer techniques, the effects of factors related to each step in the calculation procedure as well as the influence of certain pharmacokinetic parameters were studied in detail. If these factors are not well controlled, the estimated error in ka will become very large, in some cases even surpassing 30%. In addition, it was derived that careful attention has to be paid to both sampling time and the number of plasma samples. A "trial and error" method for obtaining an optimal sampling schedule that minimizes the error of ka is presented.

Intestinal Absorption↗
PubMed1983

An APL computer program for estimating rate constants of drug absorption.

The algorithm of this program for estimating rate constants of drug absorption is mainly based on the Loo-Riegelman method. In order to improve the flexibility of the program, several options for the users were included: one-, two- as well as three-compartment open models with first-order elimination; two optional methods to calculate the area under the curve, i.e. the simple trapezoidal method and the Lagrange method combined with log-trapezoidal approximation and others. In addition to the estimation of the rate constant of drug absorption, this program can be applied for the design of optimal sampling schemes. For this purpose an extra subroutine for simulating plasma drug concentration-time courses is also included.

Computers↗
PubMed1983

Avoidance of "first-pass" elimination of rectally administered lidocaine in relation to the site of absorption in rats.

The extent of "first-pass" elimination of lidocaine in relation to the site of absorption in the rectum of rats was investigated. Male Wistar rats received lidocaine orally, i.v. or rectally at 4, 2, 1 and at about 0.2 cm from the anus. In all cases 5.0 mg of a tritium-labeled lidocaine solution was administered by zero-order infusion into the rectum. In blood, unchanged lidocaine and urine and feces total radioactivity were measured. Lidocaine was absorbed almost completely in all cases as assessed relative to i.v. administration. The average elimination half-life was about the same for all routes of administration (approximately 27 min). Systemic availability of lidocaine when given by the oral route was 16%; a similar value was found after rectal administration at 4 cm distance from the anus. At 2 cm distance from the anus the mean systemic availability was 21%, at 1 cm, 45% and as closely as possible to the anus, 72%. It is concluded that the degree of avoidance of first-pass elimination of rectally administered lidocaine is very much dependent on the site of drug administration. When the drug is absorbed very closely to the anus, little first-pass elimination occurs.

Administration, Oral↗
PubMed1983

Disposition of hexobarbital in the rat. Estimation of "first-pass" elimination and influence of ether anesthesia.

The disposition of hexobarbital was studied in rats after i.v. and i.a. administration. In addition to sleeping times, plasma concentration profiles were measured. No significant differences were found in sleeping times, volumes of distribution, elimination half-lives or systemic clearances between these different routes. The average elimination half-lives were 13.5 +/- 0.8 (n = 17) and 11.6 +/- 1.9 min (n = 21) (means +/- S.E.M.), respectively, whereas the systemic whole blood clearance values were 75.4 +/- 3.4 (n = 17) and 85.8 +/- 3.5 ml/min/kg (n = 21) (means +/- S.E.M.). The values of the latter parameter approach hepatic blood flow in the rat (i.e., 100 ml/min/kg) and therefore the oral availability of hexobarbital was established by comparing areas under plasma concentration time curves, after i.v. and oral administration to the same rat. Oral availability was found to be only 36%, which corresponds to an extraction ratio of 64%. The consequences of such a "first-pass" effect are discussed in view of the use of hexobarbital as a model substrate for measuring drug-metabolizing enzyme activity. Furthermore, it was found that anesthesia as induced by diethylether during the experiments resulted in a very significant inhibition of the rate of hepatic metabolism of hexobarbital; the elimination half-life increased by about 50% due to a similar decrease in the systemic clearance. The protein binding of hexobarbital in rat plasma amounted to 51.4 +/- 1.2% (mean +/- S.E.M., n = 15) and it was found not to be dependent on the plasma concentration of hexobarbital in the range encountered in vivo.

Absorption↗
PubMed1983

Plasma concentrations of lidocaine and bupivacaine after subarachnoid administration.

Plasma concentrations were measured after subarachnoid administration of 75 mg lidocaine in a hyperbaric solution and 15 mg bupivacaine in either a hyperbaric or an isobaric solution. Peak concentration times (tmax), peak concentrations (Cmax), apparent elimination half-lives (t1/2el), and areas under the curves (AUC) were determined. The values of tmax, Cmax, t1/2el and AUC were 66 +/- 32 min, 444 +/- 203 ng/ml, 2.0 +/- 0.3 h, and 87.0 +/- 9.8 mg . 1(-1) . min, respectively, for lidocaine. Those obtained after administration of a hyperbaric bupivacaine solution were 54 +/- 11 min, 63 +/- 22 ng/ml, 3.6 +/- 1.4 h, and 19.1 +/- 5.4 mg . 1(-1) . min. Results, obtained with isobaric bupivacaine solutions, were: 86 +/- 24 min, 63 +/- 15 ng/ml, 3.2 +/- 0.4 h, and 18.1 +/- 5.4 mg . 1(-1) . min. The results indicate roughly similar absorption rates from the subarachnoid space into the general circulation after administration of hyperbaric solutions of lidocaine and bupivacaine. Bupivacaine tended to be absorbed slower when it is administered in an isobaric solution.

Adolescent↗
PubMed1982

[Comparative pharmacokinetics of 5 hypnotic benzodiazepines in healthy volunteers].

The authors have studied the pharmacokinetics of the five benzodiazepines: flurazepam, flunitrazepam, nitrazepam, temazepam and triazolam. The pharmacokinetics parameters of these molecules are different and vary according to individual sensitivity. Twelve healthy volunteers were involved in this study (6 males--6 females). The parent drug has been titrated for nitrazepam, flunitrazepam, temazepam, triazolam and the active metabolite of flurazepam, the N-desakylflurazepam (DAF). Half-lifes have been calculated: it is short for the temazepam and triazolam with no accumulation after multiple drug administration. Triazolam has the shortest half-life. Those different results enable to better understand the prescription problem of hypnotics as duration of action must be limited to one night, with no residual effect the day after.

Anti-Anxiety Agents↗
PubMed1982

Measurement of urinary metabolites of xenobiotics as a non-invasive technique in toxicology.

Most xenobiotics undergo biotransformation in living organisms and are excreted as metabolites in urine. There are three major reasons why the measurement of urinary metabolites may be important in toxicology: 1. To obtain pertinent information on the biotransformation of a compound in the body. By identifying metabolites it is often possible to assess which metabolic pathways at the enzymic level are followed and whether, for example, reactive intermediates are formed. Also quantitative and kinetic information on the disposition of a xenobiotic can be obtained. 2. To use in exposure tests (biological monitoring). The metabolites may be specific or nonspecific for the compound to which exposure takes place. 3. To use as a measure for the activity of metabolic pathways in order to assess interindividual differences in biotransformation, or to assess changes in such pathways by exposure to or ingestion of xenobiotics. In particular in the identification of genetically determined polymorphism of metabolism in man, urinary metabolites have proved to be a very useful tool. Large interindividual differences in the rate of biotransformation of xenobiotics exist and this has important biological (toxicological) implications. The possible value of measuring the urinary metabolite profile of the model compound antipyrine, as a tool in the assessment of the activity of different xenobiotic oxidizing enzymes, is discussed.

Animals↗
PubMed1982

Studies of the different metabolic pathways of antipyrine in man. Oral versus i.v. administration and the influence of urinary collection time.

The pharmacokinetics of antipyrine in plasma and saliva, and urinary excretion of its major metabolites, were studied following i.v. and oral administration of antipyrine 500 mg to 6 healthy volunteers. Data from both plasma and saliva showed that the oral bioavailability of antipyrine given as an aqueous solution was complete. The saliva/plasma concentration ratio was constant with time from about 3 h onwards, with a mean value of 0.87 after oral and 0.91 after i.v. administration. It is concluded that the pharmacokinetic parameters of antipyrine can be satisfactorily established on the basis of salivary data, although the volume of distribution and clearance values are then slightly too high. After i.v. administration, 3.8 +/- 1.9% of the dose was excreted in urine as unchanged antipyrine in 48 h, 24.9 +/- 6.3% as 4-hydroxyantipyrine, 16.5 +/- 3.2% as norantipyrine, 13.0 +/- 2.2% as 3-hydroxymethyl-antipyrine and 5.8 +/- 1.0% as 3-carboxy-antipyrine. No significant differences were observed following oral administration. The half-lives calculated from the linear part of the urinary excretion rate curves of the metabolites were about the same for oral and i.v. administration, and were of the same order of magnitude as the elimination half-life of parent drug in plasma and saliva. It is important for determination of the ultimate metabolite ratio that urine is collected for at least 36 h, because there is a delay in the excretion of 3-hydroxymethyl-antipyrine in urine.

Administration, Oral↗
PubMed1982

Zero-order rectal delivery of theophylline in man with an osmotic system.

In vivo and in vitro performances of a rectally applied osmotic delivery system containing a water-soluble derivative of theophylline were compared. The system was applied in six healthy volunteers during 72 h, and a comparison was made with two conventional dosage forms, a suppository and a solution administered orally, given once. In vitro, a perfect zero-order release rate with the osmotic system was obtained. In all subjects, application of the osmotic system resulted in a constant steady-state theophylline level just as in a long time zero-order i.v. infusion, which strongly suggests that the release rate in vivo is zero-order too. The release rate was not influenced by renewing the dosage form after 36 hr or by defecation. The in vivo and in vitro release rates were almost identical and subject-independent.

Administration, Oral↗