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Biomedical subjects

M H Bickel

Publications and source records attributed to M H Bickel.

At least 19 recordsLinked to original sources
PubMed1992

Adipose tissue distribution and chemical structure of basic lipophilic drugs: desipramine, N-acetyl desipramine, and haloperidol.

Single-dose intravenous injections of desipramine to rats resulted in a distribution pattern typical of basic lipophilic drugs, i.e., highest concentrations in lung and lowest in adipose tissue and plasma. In contrast, after N-acetyldesipramine, a non-basic analogue of desipramine with comparable lipophilicity, concentrations of this drug in adipose tissue were much higher than in lean tissue or plasma as a result of redistribution into the former and rapid disappearance from the latter tissue. N-Acetyldesipramine had much lower plasma and tissue half-lives than desipramine, but at the same time a much higher adipose/plasma concentration ratio and adipose storage index. Chronic administration of the basic lipophilic drug, haloperidol, to rats in their diet over 21 days resulted in a steady-state distribution pattern with highest concentrations in lung and lowest concentrations without accumulation in adipose tissue. This study provides additional evidence for the influence of basic groups on the distribution of lipophilic drugs. Thus, basic lipophilic drugs do not undergo redistribution into adipose tissues, possibly because of a competition by stronger binding to lean tissue as a result of lysosomotropism.

Adipose Tissue↗
PubMed1991

The use of 2,4,5,2',4',5'-hexachlorobiphenyl (6-CB) as an unmetabolizable lipophilic model compound.

2,4,5,2',4'5'-Hexachlorobiphenyl (6-CB)--a polychlorinated biphenyl (PCB) congener resistant to metabolism in most species--has become a major residue in the biosphere including human adipose tissue. Its use as a model of unmetabolizable lipophilic compounds and as a tool in toxicokinetics in the last two decades is reviewed. This extremely water-insoluble compound is transported in plasma by albumin and lipoproteins. Binding to these plasma proteins appears to be important for uptake and release processes in different tissues. The redistribution kinetics of 6-CB as well as its pronounced adipose tissue storage and a very slow excretion with the faeces has been established in long-term animal studies. Excretion is strongly influenced by an increasing or diminishing adipose storage compartment size. Other minor pathways of elimination, e.g., via hair, become also important in the absence of metabolism and renal excretion. 6-CB has revealed the possibility of an almost quantitative transfer of the maternal body burden to the offspring via milk. The use of 6-CB in studies with tissue preparations in vitro is providing insight into transport mechanisms of uptake and release.

Adipose Tissue↗
PubMed1991

Kinetics of distribution and elimination of DDE in rats.

1. Rats were given single i.v. doses of 14C-DDE, and total drug (14C) and unchanged DDE (g.l.c.) were measured for up to 14 days in blood, tissues, and excreta. The 14C recoveries amounted to 90.0 +/- 10.8 (SD) % dose. 2. DDE underwent redistribution from blood to liver, muscle, skin and, ultimately, adipose tissue. The tissue/blood concentration ratios were 6 for liver and muscle, 35 for skin, 400 for adipose tissue. Concentrations in blood and lean tissues declined biphasically with beta-half-lives of 8-12 days. The half-lives for adipose tissue and total body burden were larger by one order of magnitude. However, due to the increase of adipose tissue mass with time, the amount of DDE stored therein remained constant at almost 60% dose. 3. Except for liver, no substantial metabolite concentrations in tissues were found. In particular, lipophilic metabolites were clearly absent. Thus, tissue kinetics and storage are controlled by unchanged DDE. 4. Of a given dose of DDE, 31% was excreted in the faeces as polar metabolites within 14 days, and 3-4% dose as DDE. Urinary excretion was negligible. The beta-half-life of faecal excretion was equal to the one in blood and lean tissues. It is concluded that excretion is limited by the slow formation of polar metabolites of DDE.

Adipose Tissue↗
PubMed1990

Single-dose kinetics of tissue distribution, excretion and metabolism of amiodarone in rats.

In order to better understand the pharmacokinetic differences between acute and chronic regimens of the basic lipophilic antiarrhythmic, amiodarone (AM), a mass-balanced single-dose study ([14C]AM, 50 mg/kg, i.v.) was carried out until total elimination had been achieved (10 days). Total drug, AM and desethylamiodarone (DEA) were determined in plasma, eight tissues and excreta of rats with constant body weight. Three exponential terms were sufficient to describe the plasma concentration-time curve of unchanged AM with a long terminal half-life of 131 hr. An equally long terminal half-life of AM could also be observed in all tissues investigated. After 5 min, 42% of the radioactivity appeared in the liver, where it underwent redistribution to muscle, skin and, ultimately, adipose tissues. Whereas plasma and liver contained mainly unidentified metabolites and little DEA, unchanged AM predominated in all other tissues. According to the time-integrated parameters of distribution, AM has a potential to accumulate in adipose tissue under chronic administration. In contrast, DEA accumulation would be likely to occur in lean tissues, mainly in the lung. In 10 days, 94% of the injected radioactivity was excreted in feces and less than 2% in urine. Almost all of the excreted radioactivity consisted of unidentified metabolites, indicating that both AM and DEA are eliminated by metabolism.

Amiodarone↗
PubMed1989

What can the use of unmetabolizable lipophilic compounds tell about the importance of drug metabolism?

6-CB, a model compound which because of its lipophilicity cannot be excreted by the kidneys and is also unmetabolizable, shows an extreme type of pharmacokinetics. In rats given single doses the compound disappears with a half-life of half a life span by fecal excretion. If adipose tissue mass is allowed to increase, the 75% dose initially stored in adipose tissue does not decrease during 280 days. With repeated weekly administration each dose adds some 90% to the body burden. It is concluded that the old hypothesis of drug-metabolizing enzymes as a protective system preventing accumulation of naturally occurring lipophilic drugs is correct.

Animals↗
PubMed1988

[Side-effects of frequently administered hypnotics and sedatives as well as of anxiolytics. Results from a Comprehensive Hospital Drug Monitoring (CHDM) program].

The occurrence and age distribution of patients with adverse drug reactions (ADR) were studied on the basis of a total of 17,653 admissions to the medical divisions of the Zieglerspital Bern and the Anna-Seiler-Haus, Inselspital Bern, during the period 1976-1982. Among this population 12,424 patients (70.4%) happened to have been treated with hypnotics, sedatives or anxiolytics. Results are as follows: 1. The occurrence rate of psychic and neurologic symptoms (with the exception of somnolence and hangover) is 0.14% of all treatments if the casualty category "definitely or probably drug-induced" is considered. For "other ADR" (non-psychic, non-neurologic) the rate is 0.16%. For the benzodiazepine preparations, the psychic and neurologic ADR occurred at about the same rate as for the neuroleptic drugs studied, whereas "other ADR" related to benzodiazepines were observed in only 0.04% of treatments. 2. There is a marked difference in ADR symptoms between benzodiazepines and neuroleptics. With benzodiazepines the most severe reactions were two episodes of shortlived respiratory arrest immediately after intravenous administration. With neuroleptic drugs the most severe symptoms were choreoathetosis, dyskinesia, hyperkinesia and Parkinson's syndrome. There was no fatal reaction. 3. With benzodiazepines there is a slight but significant increase in the occurrence of psychic and neurologic symptoms in the older group of patients, as compared to the younger patients, whereas with neuroleptics there is no age dependence.

Anti-Anxiety Agents↗
PubMed1988

Differences in adipose tissue distribution of basic lipophilic drugs between intraperitoneal and other routes of administration.

1. Distribution of 14C-methadone in male rats was studied after administration of single i.p. doses. Highest concentrations were attained after 30 min in the decreasing order of abdominal adipose tissues, liver, lung, other organs. Concentrations in abdominal adipose tissues were 20 times higher than in subcutaneous adipose tissue. This is in contrast with what occurs with other routes of administrations, where only low concentrations are attained in both subcutaneous and abdominal adipose tissues. 2. The situation in the peritoneal cavity after i.p. injection was simulated in vitro by incubation of whole, excised abdominal adipose tissues of rats with methadone and other basic drugs (dibenzepine, alprenolol, opipramol, propranolol, chlorpheniramine, desipramine, imipramine and chlorpromazine) for 6 h at pH 7.4. These drugs were readily taken up (25 to 74% at equilibrium). 3. There was a positive correlation between uptake and lipophilicity of the drugs as measured by log P (octanol/water). Less lipophilic drugs such as amphetamine, morphine and chlorphentermine were not appreciably taken up from the incubation medium. The threshold log P-value for appreciable adipose tissue uptake is around 2. 4. It is concluded from these data and related studies that basic lipophilic drugs are not stored in adipose tissues in vivo, except when given via the i.p. route. In the latter case the storage appears to result from non-systemic, diffusional uptake from the peritoneal cavity.

Adipose Tissue↗
PubMed1987

Tissue distribution of phenoxybenzamine in the rat. Lack of adipose tissue storage.

Rats were given the basic lipophilic drug, phenoxybenzamine, in single i.v. doses of 0.4 and 30 mg/kg. The drug was determined in plasma and 7 tissues by a new HPLC method. Adipose tissue reached peak levels after 30 minutes. At that time levels in heart, kidney, and brain were higher than in subcutaneous, epididymal, and mesenteric adipose tissues. The percentage metabolites in adipose tissue, kidney, and liver was 0, 88, and 96, respectively. Pretreatment with SKF 525-A inhibited metabolism and increased the tissue levels of unchanged drug, however, even under these conditions storage in adipose tissues did not occur, the adipose storage index being still less than unity. These results contradict findings of the 1950s which have been repeatedly reported in textbooks and reviews, but they confirm observations that basic drugs, even when highly lipophilic, are not being stored in adipose tissues.

Adipose Tissue↗
PubMed1987

Characterization of drug distribution and binding competition by two-chamber and multi-chamber distribution dialysis.

Binding competition between blood and tissue, a determinant of drug distribution, can be simulated and quantitated in vitro by distribution dialysis. In a study with a standardized two-chamber system, six model drugs, selected according to their ratio of plasma to tissue binding, were allowed to distribute between blood and eight tissue homogenates of rats. The tissue:blood concentration ratios were 1 for antipyrine, less than 1 for salicylic acid and phenylbutazone, slightly greater than 1 for pentobarbital and thiopental, and much greater than 1 for imipramine. Comparable values of tissue:blood ratios were obtained in rats in vivo. A modified dialysis system was developed which allows the simultaneous distribution of a drug between blood and four tissue homogenates. This multi-chamber system was used for homogenates of liver, lung, muscle, and adipose tissue. The drugs tested reached a first apparent distribution equilibrium after 2.5 to 4 h, comparable with the distribution in the two-chamber system, as a result of tissue:blood binding competition. In the following hours there was a redistribution as a result of binding competition among individual tissues, except in the case of pentobarbital. A minor redistribution from muscle to adipose tissue was observed with phenylbutazone, and from muscle to liver with imipramine. There was a considerable redistribution from all tissues, including blood, to adipose tissue with thiopental. In a sequential mode of operation this multi-chamber system was used to simulate the influence of the different perfusion rates of individual tissues by adding the homogenates of muscle and/or adipose tissue several hours after the other tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding, Competitive↗
PubMed1986

[Acute and chronic toxicity of psychotropic drugs].

Within psychotropic drugs acute toxicity is highest in antidepressants (thymoleptics, MAO-inhibitors, lithium), lower in neuroleptics, and very low in anxiolytics. The order of decreasing chronic toxicity is: neuroleptics, antidepressants, anxiolytics. Each class of psychotropic drugs has a specific toxicological problem. With anxiolytics the major problems stem from their misuse and overuse. With neuroleptics tardive dyskinesia is a serious threat to longterm therapy. Finally, antidepressants are characterized by a low therapeutic index and a resulting high incidence of severe and fatal poisoning cases, both intentional and accidental.

Anti-Anxiety Agents↗
PubMed1986

Uptake of lipophilic model compounds into the isolated perfused rat epididymal adipose tissue.

Uptake of xenobiotics into isolated perfused rat adipose tissue was studied. Aorta and vena cava were cannulated and ligations were placed so that only an epididymal fat pad was perfused. Perfusion experiments were performed in situ and nonrecirculating, for up to 350 min, with Krebs-Ringer bicarbonate buffer containing 4% serum albumin. The functionality of the preparation was tested by an after-perfusion with methylene blue as well as with the volume and mass balances. Formation of edema was not a problem under the experimental conditions used. The following model compounds were used at influx concentrations of 2 to 8 microM: thiopental, imipramine, chlorpromazine, 1,1-bis-(p-chlorophenyl)-2,2-dichloroethane (DDE) and 2,4,5,2',4',5'-hexachlorobiphenyl (6-CB). Uptake was determined during the experiments using the arteriovenous difference and after the experiments by direct determination in the perfused fat pad. All five model compounds were taken up readily. Rate of uptake tended to decrease initially and to reach a constant value. Only with 6-CB was the difference between initial and terminal rate considerable. Mean uptake fraction was: thiopental, 38 +/- 8%; imipramine, 69 +/- 4%; chlorpromazine, 85%; DDE, 56%; and 6-CB, 13 +/- 1%. Thus, imipramine and chlorpromazine, which do not accumulate in adipose tissue in vivo, are even taken up more rapidly into the isolated perfused adipose tissue than is thiopental. The difference between these two experimental situations is therefore not due to a permeability barrier, but rather to factors outside the adipose tissue, such as competing nonadipose tissues present in vivo only. For the neutral, insoluble and almost totally albumin-bound compounds, DDE and 6-CB, albumin may act as an additional binding competitor that inhibits adipose tissue uptake.

Adipose Tissue↗
PubMed1985

Uptake in vitro of lipophilic model compounds into adipose tissue preparations and lipids.

In vitro uptake of 11 lipophilic model compounds into rat epididymal adipose tissue slices, adipocytes, triglycerides, and lecithin was studied. Relative uptake at equilibrium into adipose tissue slices increased from 6 to 87% in the following sequence: phenazone, morphine less than pentobarbital less than glutethimide, phenylbutazone less than thiopental, methadone less than chlorpromazine, imipramine. In the presence of albumin a similar sequence was obtained at lower uptake levels, with DDE and 2,4,5,2',4',5'-hexachlorobiphenyl (6-CB) on top with 95% uptake. However, the time to reach equilibrium was unproportionately greater for DDE and 6-CB (16-40 hr) than for other compounds (1-4 hr). A linear positive correlation was found between relative uptake and partition coefficient (octanol/water). Relative uptake was independent of drug concentration. There were no significant differences between uptake values measured with adipose tissue slices, adipocytes, triolein, and a saturated short-chain triglyceride. In contrast, uptake into lecithin was not correlated with the octanol partition coefficient. Thiopental, imipramine, and 6-CB were taken up into lean tissue slices (liver, lung, skin) in excess of their lipid content, suggesting additional binding sites. Release from preloaded adipose tissue slices followed first order kinetics, was accelerated by albumin, and was much slower for 6-CB and DDE than for thiopental and imipramine. The results indicate that uptake of lipophilic xenobiotics in vitro is a partition process between the aqueous medium and the triglyceride of the adipose tissue preparation. In contrast, the extent of adipose tissue storage of drugs in vivo has recently been shown not to correlate with octanol partition coefficients.

Adipose Tissue↗
PubMed1985

Comparative adipose tissue kinetics of thiopental, DDE and 2,4,5,2',4',5'-hexachlorobiphenyl in the rat.

A comparative study on the fate of thiopental, DDE, and 2,4,5,2',4',5'-hexachlorobiphenyl (6-CB) with emphasis on adipose tissue kinetics was carried out after single i.v. doses to adult male rats. The time course of the concn. in blood, adipose and other tissues were determined for the three compounds for periods up to 40 h, 14 and 28 d, respectively, allowing for mass balances and for calculation of pharmacokinetic parameters. Appreciable amounts of thiopental, DDE and 6-CB appeared in adipose tissues, but the kinetics were profoundly different, the adipose tissue concn. peaking after one hour, 17 h, and five to six weeks, respectively. Thus, although DDE and 6-CB are much more lipophilic than thiopental, they were very much slower in entering adipose tissue. The results indicate that adipose tissue storage of drugs and other xenobiotics cannot be explained as a simple partition phenomenon. Rather, disposition in adipose tissue may be determined by initial binding in other tissues.

Adipose Tissue↗
PubMed1979

A method to estimate binding constants at variable protein concentrations.

The association constants of the binding of chlorpromazine and imipramine to serum albumin at low saturation of the protein were determined by a new experimental approach with the protein concentration rather than the ligand concentration being varied. This approach is suitable for estimating binding constants in systems with one class of binding sites. In addition, the method is proposed to complement conventional binding studies of systems with two classes of binding constant with higher accuracy.

Chlorpromazine↗
PubMed1979

Interference of UDP-glucuronyltransferase and beta-glucuronidase activity in rat liver microsomes at pH 7.5 with p-nitrophenol and p-nitrophenylglucuronide as substrates.

Microsomal fraction contains the whole of hepatic UDP-glucuronyltransferase as well as part of beta-glucuronidase. The activities of the two enzymes were assayed under identical conditions using untreated male rat liver microsomes at pH 7.5. In a 30-min incubation with p-nitrophenol and UPD-glucuronic acid, a net glucuronide formation of 0.010 mumol.min-1.g.liver-1 was measured. In the presence of saccharolactone at concentrations selectively blocking beta-glucuronidase, the glucuronidation rate was 0.015 mumol.min-1.g.liver-1. Using the kinetic parameters of beta-glucuronidase (Km = 0.06 mmol/l p-nitrophenylglucuronide, Vm = 0.075 mumol pNP formed.h-1.g.liver-1) determined in the absence of UDP-glucuronic acid, to correct for the beta-glucuronidase's interference on the glucuronidation process, a glucuronide formation of 0.011 mumol.min-1.g.liver-1 was calculated.

Animals↗