Clinical pharmacokinetics of hypnotics.
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Amobarbital↗
Biomedical subjects
D D Breimer
Publications and source records attributed to D D Breimer.
Therapeutic drug monitoring in saliva.
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Antipyrine↗
Clinical pharmacokinetics of nitrazepam.
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Biotransformation↗
Rectal drug administration: clinical pharmacokinetic considerations.
The human rectum represents a body cavity in which drugs can be easily introduced and retained and from which absorption is well possible. There are important therapeutic reasons why it is sometimes preferable to give a drug rectally rather than orally, e.g. in cases of nausea and vomiting. Drawbacks of rectal drug administration include the interruption of absorption by defaecation and lack of patient acceptability. The mechanism of drug absorption from the rectum is probably no different to that in the upper part of the gastrointestinal tract, despite the fact that the physiological circumstances (e.g. pH, fluid content) differ substantially, Absorption from aqueous and alcoholic solutions may occur very rapidly, which has proved to be of considerable therapeutic value in the rapid suppression of acute convulsive attacks by diazepam (e.g. in children), but absorption from suppositories is generally slower and very much dependent on the nature of the suppository base, the use of surfactants or other additives, particle size of the active ingredient, etc. There is some evidence that hepatic first-pass elimination of high clearance drugs is partially avoided after rectal administration, e.g. lignocaine. This can be explained by the rectal venous blood supply: the upper part is connected with the portal system, whereas the lower part is directly connected with the systemic circulation. Plasma concentration data following rectal administration of representatives of several classes of drugs are reviewed: anticonvulsants, non-narcotic analgesics and non-steroidal anti-inflammatory agents, hypnosedatives and anaesthetics, strong analgesics, theophylline and derivatives, corticosteroids, antibacterial agents, thiazinamium, promethazine, hyoscine-N-butyl-bromide, streptokinase, progesterone, ergotamine tartrate and levodopa. Only limited number of cases has it been adequately shown that the rectal route of administration gives plasma concentrations which are comparable to the oral route. Potentially the rectal route offers the same possibilities as the oral route, but the influence of the formulation seems to be very critical. It is also likely that the future novel drug delivery systems with zero order release characteristics will be applied rectally. Interesting preliminary results have already been obtained with theophylline administered by 2ml osmotic pumps.
Adrenal Cortex Hormones↗
Interindividual variations in drug disposition. Clinical implications and methods of investigation.
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Animals↗
Influence of haemodialysis on the pharmacokinetics and haemodynamic effects of nifedipine during continuous intravenous infusion.
The pharmacokinetics and haemodynamic effects of nifedipine were studied in 5 patients on long term haemodialysis. In addition, clearance of the drug on 2 different types of artificial kidneys were measured in vitro. Nifedipine was administered intravenously (1.3 mg/h) from 6 hours before starting haemodialysis to the end of haemodialysis, performed according to the standard protocol of each patient. Before and during haemodialysis, blood samples were taken for determination of free and total plasma nifedipine concentrations. Recovery was determined by measuring nifedipine concentrations in the dialysate. Heart rate and systolic and diastolic blood pressures were determined serially. The haemodynamic changes during nifedipine were compared with those of 3 previous dialysis sessions. Haemodialysis was accompanied by a slight decrease in steady-state nifedipine concentrations. The recovery in dialysate varied between 0.6 and 0.9% of the amount infused during the period of dialysis. Artificial kidney clearance of nifedipine varied between 2.8 and 8.3 ml/min, which was in agreement with in vitro data. Changes in steady-state nifedipine concentrations were most likely due to changes in systemic clearance caused by haemodialysis itself. Systolic and diastolic blood pressure dropped by approximately 15% and 25%, respectively, in comparison with dialysis without nifedipine, but changes in heart rate were not different. It is concluded that nifedipine is poorly dialysable. During haemodialysis, blood pressure is markedly reduced but dose schedules need not to be changed.
Adult↗
Metabolism of simultaneously administered antipyrine and theophylline in male BN/BiRij rats before and after induction with 3-methylcholanthrene.
In order to study the metabolic activities of different P-450 enzymes in male Brown Norway rats, formation rates of antipyrine (AP) metabolites and theophylline (TH) metabolic clearance were determined. Brown Norway rats are often used in studies concerning the influence of age on liver function. Experiments were performed after simultaneous iv administration of the two compounds with and without 3-methylcholanthrene (3-MC) pretreatment. Pharmacokinetic data of both AP and TH were significantly influenced by 3-MC pretreatment. Metabolic clearance of AP increased from 6.8 +/- 1.0 (mean +/- SD, N = 23) to 18.4 +/- 7.9 (N = 10) ml.min-1.kg-1, whereas the metabolic clearance of TH increased from 1.9 +/- 0.6 to 20.0 +/- 5.1 ml.min-1.kg-1. Elimination half-life in plasma decreased from 77 +/- 10 to 33 +/- 9 min for AP and from 171 +/- 36 to 25 +/- 7 min for TH, respectively. Urinary recovery as the metabolites 3-hydroxymethylantipyrine, 4-hydroxyantipyrine, and norantipyrine accounted for approximately 36% of the administered dose in the control situation, and for approximately 21% after 3-MC pretreatment. 3-MC pretreatment strongly reduced the formation of 3-hydroxymethylantipyrine, but increased the formation rate of 4-hydroxyantipyrine and norantipyrine. Weak correlations were found between the clearances of formation of the AP metabolites and the metabolic clearance (CLm) of TH in the control rats. This may be caused by a large contribution of constitutive P-450 enzymes in the formation of AP metabolites and/or the metabolic clearance of TH in Brown Norway rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Dose-dependent pharmacokinetics of zoxazolamine in the rat.
Zoxazolamine (ZX) is a model substrate frequently used in studies on (methylcholanthrene-inducible) hepatic cytochrome P-450 activity. The iv pharmacokinetics of ZX were studied in rats at four dose levels: 5 mg X kg-1 (n = 6), 25 mg X kg-1 (n = 6), 50 mg X kg-1 (n = 5), and 60 mg X kg-1 (n = 4). Concentrations of ZX in blood, as well as the urinary excretion of unchanged ZX and chlorzoxazone, were determined. The apparent systemic clearance (CLs,app) decreased with increasing dose from 52.6 +/- 3.9 at 5 mg X kg-1 to 9.3 +/- 0.4 ml X min-1 X kg-1 at 60 mg X kg-1. The apparent elimination half-life, t1/2,app, increased from 16.1 +/- 0.3 min to 141 +/- 28.5 min. There was only slight concentration dependency of plasma protein binding: 86.0 +/- 0.9% at 4.2 +/- 0.2 micrograms X ml-1 (n = 6) vs. 80.4 +/- 0.4% at 27.1 +/- 1.1 micrograms X ml-1 (n = 6). Since from clearance and protein binding data nonrestrictive clearance of ZX could be inferred, this small change in binding was regarded as irrelevant for the interpretation of pharmacokinetic data of ZX. The blood-plasma concentration ratio was larger than unity: 2.11 +/- 0.09 at 5.4 +/- 0.9 micrograms X ml-1, and 1.85 +/- 0.08 at 47.9 +/- 4.9 micrograms X ml-1 (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Biotransformation of 1,2-dibromopropane in rats into four mercapturic acid derivatives.
1,2-Dibromopropane was administered orally in doses of 50-350 mg/kg to male Wistar rats. Four mercapturic acids were identified in urine by GC/MS, viz. N-acetyl-S-(2-oxopropyl)-L-cysteine (I), N-acetyl-S-(2-hydroxypropyl)-L-cysteine (II), N-acetyl-S-(1-carboxyethyl)-L-cysteine (III), and N-acetyl-S-(2-bromo-2-propenyl)-L-cysteine (IV). Mercapturic acid IV was a minor metabolite which could only be measured at doses of 200 mg/kg or higher. In 24 hr, urinary excretion of mercapturic acids amounted to about 36% of the dose (11% I, 21% II, 4% III, 0.2% IV). No dose dependency was found up to the highest dose. A unified scheme is proposed for the metabolism of 1,2-dibromopropane in the rat, which accounts for the identified mercapturic acids. The role of direct glutathione conjugation in the route leading to the major metabolite II, presumably involving thiiranium ion formation, is discussed. This route probably is biologically not very important because of the absence of detectable activity of 1,2-dibromopropane toward glutathione S-transferases in vitro, the very low mutagenicity of 1,2-dibromopropane, and the high mutagenic activity of N-acetyl-S-(2-bromopropyl)-L-cysteine methyl ester which was studied as a model compound for direct conjugation.
Acetylcysteine↗
Glutathione conjugation of 1,2-dibromo-1-phenylethane in rats in vivo.
The metabolism of 1,2-dibromo-1-phenylethane (DBPE) was studied in rats. Administration of DBPE orally, in doses of 0.25-1.25 mmol/kg (66-330 mg/kg), to male Wistar rats resulted in the excretion of a single mercapturic acid in urine. The methyl esters of three potential mercapturic acid metabolites were synthesized: N-acetyl-S-(2-oxo-2-phenylethyl)-L-cysteine methyl ester (O),N-acetyl-S-(2-hydroxy-1-phenylethyl)-L-cysteine methyl ester (I), and N-acetyl-S-(2-hydroxy-2-phenylethyl)-L-cysteine methyl ester (II). GC/MS analysis showed that the methyl ester of the excreted mercapturic acid was identical with II. Quantitative measurement of II in urine by GLC showed that, after 24 hr, excretion of the mercapturic acid was almost complete and amounted to 41% of the administered dose. At doses higher than 1.00 mmol/kg, the excretion no longer increased. Inhibition of the oxidative pathways by ip injection of 1-phenylimidazole resulted in an excretion decrease of about 40%. (Pre)treatment with diethyl maleate lowered the excretion of mercapturic acid by 30-60%. Glutathione conjugates synthesized from DBPE and styrene oxide were separated by HPLC. Both compounds can produce the same two pairs of diastereomers, viz. (R)- and (S)-(2-hydroxy-1-phenyl-ethyl)glutathione ((R)-1 and (S)-1), and (R)- and (S)-(2-hydroxy-2-phenylethyl)glutathione ((R)-2 and (S)-2). These could be separated in the order (R)-2, (R)-1, (S)-1, and (S)-2 within 20 min. This method was also applied to examine glutathione conjugates excreted in bile after DBPE administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcysteine↗
Dose-dependent stereoselectivity in the formation of mercapturic acids from cyclohexene oxide by the rat.
Rats dosed with cyclohexene oxide excreted only two of the four possible isomeric N-acetyl-S-2-hydroxycyclohexyl-L-cysteines, the two diastereoisomers of N-acetyl-S-(trans-2-hydroxycyclohexyl)-L-cysteine. No trace of the corresponding two cis-2-hydroxy compounds was found by use of 1-HNMR, 13-CNMR, or GLC methods. A rapid and selective GLC method was developed to assay the ratio and concentrations of the two trans-mercapturic acids. Up to a dose of 0.5 mmol of cyclohexene oxide per rat, 21 +/- 4% of the dose was excreted as mercapturic acid. At higher doses the amount of mercapturic acid excreted remained constant, presumably because of the exhaustion of the glutathione supply in the body. The ratio of trans-diastereoisomers was found to vary from 6:1 at low doses to 3:1 at high dose, implying that the formation of mercapturic acids initially occurs with a high degree of stereoselectivity.
Acetylcysteine↗
Formation of mercapturic acids from acrylonitrile, crotononitrile, and cinnamonitrile by direct conjugation and via an intermediate oxidation process.
After administration of acrylonitrile, crotononitrile and cinnamonitrile to rats, two types of mercapturic acids were isolated from urine and identified by mass and NMR spectroscopy as N-acetyl-S-(2-cyanoethyl)-L-cysteine (I) and N-acetyl-S-(2-hydroxyethyl)-L-cysteine (II) (methyl-substituted in the case of crotonitrile and phenyl-substituted in the case of cinnamonitrile). After pretreatment of rats with the cytochrome P-450 inhibitor 1-phenylimidazole, no trace of mercapturic acid II was found, whereas a higher amount of mercapturic acid I was excreted. It is suggested that the first type of products result from direct addition of glutathione, whereas the second group of metabolites (II), in which the cyano group has been replaced by a hydroxyl group, are formed via an intermediate epoxide. Substituents on the double bond had a considerable influence on the ratio of the two mercapturic acids formed, and thus presumably on the amount metabolized via an oxidative process: the ratio of the cyano (I) to hydroxy (II) mercapturic acid was 72:28 for AN; introduction of a methyl or a phenyl group resulted in ratios of 91:9 and 98:2, respectively.
Acetylcysteine↗
Induction of hexobarbital and antipyrine metabolism by rifampicin treatment in the pig.
The rates of antipyrine and hexobarbital elimination from blood or plasma were used to determine whether the antibiotic rifampicin is an inducer of microsomal oxidative drug metabolism in the pig. Treatment with rifampicin (300 mg, po, twice daily for 7 days) decreased hexobarbital and antipyrine elimination half-lives by 65 and 62%, respectively. This was associated with an increase of the metabolic clearance by 222% for hexobarbital and 255% for antipyrine. However, not in all pigs was an increase of antipyrine clearance observed. The antipyrine metabolite profile was determined before and after rifampicin treatment. The partial clearance of 4-hydroxyantipyrine, as measured on the basis of urinary excretion data, increased about fourfold. Neither norantipyrine nor 3-hydroxymethylantipyrine were detectable in urine before rifampicin treatment. Only after rifampicin treatment could a small amount of 3-hydroxymethylantipyrine be measured. It is concluded that rifampicin is a potent inducer of microsomal oxidative drug metabolism in the pig. In contrast to other animal species, the pig seems to represent a suitable animal model for further study of rifampicin induction. Because of the increase of hexobarbital clearance in all cases and lack of increase of antipyrine clearance in some pigs, a similarity between the situation in man and pig seems to exist.
Animals↗
Disposition of hexobarbital enantiomers in the rat.
The enantiomers of hexobarbital (HB), designated as (+)-HB and (-)-HB, were administered orally to separate groups of rats. Blood concentration-time curves of the parent compounds and the metabolites 3'-hydroxyhexobarbital (OH-HB) and 3'-ketohexobarbital (K-HB) were determined, as well as the cumulative urinary excretion of unconjugated OH-HB, K-HB, and 1,5-dimethylbarbituric acid (DMBA). The t1/2,(+)-HB was 13.4 +/- 0.8 min, and the t1/2,(-)-HB was slightly longer, 16.7 +/- 0.6 min (mean +/- SEM, N = 6). The intrinsic clearance values, CLint,(+)-HB and CLint,(-)-HB, were 2947 +/- 358 and 411 +/- 65 ml min-1 kg-1, respectively. The extraction ratios (E) were 0.94 for (+)-HB and 0.68 for (-)-HB. The t1/2,OH-(+)-HB and t1/2,OH-(-)-HB as calculated from blood data, were nearly the same: 20.0 +/- 2.6 and 22.2 +/- 1.5 min, respectively. Such data could not be established for the K-HB metabolites, since the curves exhibited no clear elimination phase. DMBA was undetectable in blood. The cumulative excretion of the measured metabolites in 24-hr urine was 44.0 +/- 1.8% for (+)-HB and 78.9 +/- 2.9% for (-)-HB, which was predominantly due to a substantial difference in the percentage of K-HB excreted. It is concluded that, to apply HB as a model substrate to assess oxidative enzyme activity, the use of only (-)-HB should be preferred to (+)-HB or (+/-)-HB because of a lower intrinsic clearance and a more complete recovery of oxidized metabolites in urine.
Animals↗
The blood-brain barrier: clinical implications for drug delivery to the brain.
The blood-brain barrier (BBB) determines whether or not a given drug can reach the central nervous system (CNS), either by passive diffusion or through carrier or receptor systems. Initial work focused on the structural and physico-chemical requirements favouring transport across the BBB as related to anatomical and physiological features. Such studies have had a significant effect on the design of CNS-active drugs with improved permeability across the BBB. Progress in pharmacology and neurosciences resulted in greater knowledge of CNS diseases and of potential therapies, but also created the need to develop new strategies to improve drug delivery to the brain. For a long time the BBB was considered to be a physical barrier, mainly represented by the cerebrovascular endothelium; however, transport of drugs to the brain may be limited by the metabolic activity of the BBB. The BBB should be regarded as a dynamic rather than a rigid barrier; it can be influenced by astrocytes and probably also by neuronal and hormonal stimuli, and its properties are also affected by diseases of the CNS. This may offer new strategies for targeting drugs to the brain.
Biological Transport↗