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Biomedical subjects

W Kalow

Publications and source records attributed to W Kalow.

At least 91 records · Page 5Linked to original sources
PubMed1988

Oxazepam as a probe of hepatic metabolism in patients with Alzheimer's disease.

1. Hepatic metabolism of oxazepam in Alzheimer's disease (AD) was assessed by measurement of urinary metabolites in a group of hospitalized patients with AD, a hospitalized schizophrenic control group and a normal community based group. 2. A subgroup of six AD patients showed marked elevations of the hydroxylated metabolite. The median excretion of conjugated oxazepam in the AD and schizophrenic patients was almost one third that in normal controls (p less than .005). 3. A relationship between decline in level of conjugated metabolite and increase in the mental confusion score on the London Psychiatric Rating Scale (r = -.5253, p less than .05) was found in the AD patients. 4. Changes in hepatic metabolism in AD may be relevant not only for drug metabolism and the development of side effects, but also for the pathogenesis of AD.

Aged↗
PubMed1987

Biotransformation of caffeine by microsomes from human liver. Kinetics and inhibition studies.

The nature of the cytochrome P-450-dependent enzyme reactions giving rise to four primary metabolites of caffeine was investigated using microsomes isolated from livers of human kidney donors. Metabolite formation proceeded at a lower rate than that predicted from in vivo caffeine elimination half-lives, as has been observed in other species using this compound as a substrate in microsomal incubations. Kinetic experiments indicated that the formation of each of the N-demethylated metabolites paraxanthine, theobromine and theophyline was mediated by both a high- and a low-affinity catalytic site over a substrate concentration range from 0.05 mM to 80.0 mM, although only the high-affinity component is likely to be of any importance at normally encountered in vivo caffeine concentrations. 7-Ethoxyresorufin and acetanilide, selective substrates for two polycyclic aromatic hydrocarbon (PAH)-inducible isozymes of cytochrome P-450 in the mouse (P1-450 and P3-450, respectively) were each able to inhibit competitively the formation of caffeine metabolites by human liver microsomes, while caffeine could in turn similarly inhibit the biotransformations of these two compounds. The isozyme-selective P-450 inhibitor alpha-naphthoflavone (ANF) potently inhibited the high-affinity component of caffeine N-demethylations, while 1-phenylimidazole (PI) was a more potent inhibitor of the low-affinity component. The inhibition studies also indicated that the formation of 1,3,7-trimethyluric acid was mediated by both ANF-sensitive and PI-sensitive sites. Taken together, the data support suggestions from in vivo studies that a PAH-inducible isozyme of cytochrome P-450 plays a significant role in the biotransformation of caffeine in man.

Adult↗
PubMed1987

Genetic variation in the human hepatic cytochrome P-450 system.

Studies in rodents indicate that the cytochrome P-450 system consists of a superfamily of heme proteins, produced by clusters of structural genes on different chromosomes. Equivalent P-450s of different species show more homologies than members of different P-450 families within a species. The Ah receptor serves the induction of members of one of the cytochrome families. The human structural gene for the methylcholanthrene-inducible P1-450 is located on Chromosome 15. This gene has been completely sequenced. The human Ah receptor is also measurable. New methods to measure inducibility in man involve new lymphocyte bioassays and mRNA determinations, while in vivo biotransformation studies of caffeine allow estimates of the state of induction. Structural genes for phenobarbital-inducible cytochromes have been localized to Chromosome 19. The deficiency of biotransformation of debrisoquine and sparteine continues to be explored intensely. Linkage studies indicate the gene for the variable cytochrome P-450 to be located on Chromosome 22. The deficiency is more likely due to structural variation than absence of the cytochrome. Inhibiting drugs can mimic the genetic defect. Many pharmacological and toxicological consequences of the deficiency have been defined. The main characteristics of the genetic deficiencies affecting the metabolisms of mephenytoin, phenytoin, tolbutamide, nifedipine and of methyl cysteine were outlined briefly.

Animals↗
PubMed1987

A urinary metabolite ratio that reflects systemic caffeine clearance.

Systemic caffeine clearance and urinary metabolite profiles were determined in 15 subjects with diverse exposure histories to cytochrome P-450 inducers (cigarette smoke) and inhibitors (oral contraceptive steroids). A correlation was observed between caffeine clearance and a urinary ratio based on the molar recovery of paraxanthine 7-demethylation products relative to a paraxanthine 8-hydroxylation product (r = 0.91; P less than 0.001). Analysis of urinary metabolites was undertaken in a larger population to assess the effects of gender, age, oral contraceptives, and smoking on the ratio. No gender differences were observed in either adults or children; children (n = 21) showed a higher (P less than 0.001) mean metabolite ratio than adults (n = 61), oral contraceptive users (n = 9) had lower (P less than 0.05) ratios than women not taking oral contraceptives (n = 30), and smokers (n = 26) had higher (P less than 0.001) ratios than nonsmokers (n = 61). The data indicate that a urinary metabolite ratio based on paraxanthine 7-demethylation/8-hydroxylation products reflects systemic caffeine clearance and likely monitors cytochrome P-450 activity inducible by polycyclic aromatic hydrocarbons.

Adult↗
PubMed1987

An alternative test for acetylator phenotyping with caffeine.

Previously published methods allow the determination of the genetically controlled acetylator status using caffeine as a test drug, based on the urinary excretion of a ring-opened metabolite of caffeine, an acetylated uracil (5-acetylamino-6-formylamino-3-methyluracil). 5-Acetylamino-6-formylamino-3-methyluracil is labile but can be converted into a stable, deformylated product referred to as 5-acetylamino-6-amino-3-methyluracil, which has recently been shown to be quantifiable by exclusion chromatography. The first part of the present article represents a longitudinal study of three subjects to assess the intraindividual variability of those caffeine metabolite ratios that are of potential interest for the determination of acetylator phenotypes. Effects of single and multiple doses, as well as of different periods of urine collection, were tested. A ratio relating the excretion of 5-acetylamino-6-amino-3-methyluracil to that of all products of the 7-demethylation pathway of paraxanthine proved to be highly reproducible, particularly after collection of overnight urine after coffee consumption during the day. This ratio showed complete concordance with the plasma index for sulfamethazine acetylation. The second part of this article showed the use of this ratio in a population study. It allowed a good separation of slow and fast acetylators and probably also a separation of homozygous and heterozygous fast acetylators.

Acetylation↗
PubMed1987

Drug therapies as sources of information about alcoholism.

This report touched three aspects of drug therapy in alcoholics. The first topic consisted of a comparison between the effects of disulfiram treatment with the consequences of inborn deficiency of aldehyde dehydrogenase isozyme I; the comparison generated some concepts which might be subject to observational verification. The second topic was the citation of studies which suggest a selective decrease of the appetite for alcohol by drugs classified as serotonin uptake blockers. Finally, I cited the presently revealed success of propylthiouracil treatment of alcoholics suffering from liver damage, a success measured not only in laboratory terms but in terms of patient survival.

Alcoholism↗
PubMed1986

Genetics of drug transformation.

Biotransformations of drugs are controlled or strongly affected by genetic factors. During the past few years several genetic deficiencies of drug-metabolizing reactions catalyzed by members of the family of cytochrome P-450 were observed. Choice of the appropriate drug to study and attention to urinary metabolites have been the essential ingredients for the recent discovery of genetic deficiencies of drug metabolism in man which include recessive deficiency of debrisoquine/sparteine metabolism and of mephenytoin metabolism. The clinical significance of these defects is discussed. Ethanol after metabolism to acetaldehyde is further metabolized to acetic acid by aldehyde dehydrogenase. Numerous isozymes of aldehyde dehydrogenase exist, one of which possesses a high affinity for acetaldehyde. Approximately 40% of the Oriental population lack this high affinity isozyme so that in these individuals who may have symptoms of flushing and other unpleasant effects the acetaldehyde formed is destroyed only at high plasma concentrations.

Alcoholism↗
PubMed1986

Effect of allopurinol on caffeine disposition in man.

Caffeine (5 mg kg-1) was administered orally to two healthy, non-smoking subjects on three separate occasions--before, and during therapy with the xanthine oxidase inhibitor allopurinol at doses of either 300 or 600 mg daily. Plasma and urinary levels of methylxanthines, endogenous oxypurines and allopurinol and its metabolite oxypurinol were measured using h.p.l.c. analyses. Allopurinol treatment caused a specific, dose-dependent inhibition of the conversion of the caffeine metabolite 1-methylxanthine (1X) to 1-methyluric acid (1U). A good correlation was observed in both subjects between the urinary 1U/1X molar ratio and the ratio of endogenous urate to hypoxanthine + xanthine at the different allopurinol doses, supporting the proposal that the 1U/1X molar ratio after caffeine intake provides an in vivo index of xanthine oxidase activity in man.

Adult↗
PubMed1986

The genetic defect of mephenytoin hydroxylation.

The antiepileptic drug mephenytoin is a racemate. Mephenytoin hydroxylation is a stereospecific reaction and is confined to the S-enantiomer, which is normally eliminated within hours, allowing the R-enantiomer to accumulate since it can be eliminated only within days or weeks. The inborn deficiency of this hydroxylase prevents the rapid elimination of S-mephenytoin causing it to linger in the body along with R-mephenytoin. Thus, the normal hydantoin levels in blood are doubled with corresponding toxic sequelae. Studies in vitro with liver preparations derived from kidney donors indicate that the hydroxylation depends on a single catalytic site of cytochrome P-450. Sixty-four drugs were screened for their ability to bind to this genetically variable cytochrome, using inhibition studies. The small group of drugs with some ability to bind to mephenytoin hydroxylase included benzodiazepines and inhibitors of mono-amino-oxidase. At this time, there is no clinical evidence that the hydroxylation deficiency of mephenytoin affects any other drug. The sum of data from various authors indicates a frequency of poor metabolizers of 4.8% (1.9-8.0% at a 99.6% confidence range) among 459 persons of European extraction. There were seven poor metabolizers among 31 Canadians of Japanese extraction (23%), and two among 39 Canadian Chinese (5%).

Aryl Hydrocarbon Hydroxylases↗
PubMed1986

Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity.

Individual differences in metabolism of the sulfonamides may predispose patients to idiosyncratic reactions. Sulfonamides are metabolized by N-acetylation (mediated by a genetically polymorphic enzyme) and oxidation to potentially toxic metabolites. We examined 6 patients who had severe reactions to sulfonamides and compared them with 20 controls. Acetylator phenotype was determined with caffeine, a safe in-vivo probe of enzyme activity. All 6 patients were slow acetylators (expected, 55%; p less than 0.05). Detoxification of oxidative metabolites was studied in vitro with a lymphocyte assay evaluating cell death from metabolites generated by a murine hepatic microsomal system. Cells from each patient showed increased toxicity from sulfonamide metabolites but not from the drugs themselves. Cells from parents of 3 patients had intermediate toxicity from sulfonamide metabolites, whereas cells from a sibling of 1 patient had a normal response. Susceptibility to sulfonamide reactions may be due to interaction of metabolic pathways, possibly under genetic control, regulating N-acetylation and specific detoxification of toxic metabolites of the drugs.

Acetylation↗
PubMed1986

Ethnic differences in reactions to drugs and xenobiotics. Caffeine and other drugs.

I have presented some diverse case reports which illustrate several variations on the theme of this conference. A study of caffeine metabolites revealed two kinds of interethnic variation, one pertaining to the well-known acetylation polymorphism affecting the secondary metabolism of the parent drug; the other consisted of a difference in paraxanthine excretion which might indicate an ethnic difference in renal function. Older data on the pharmacokinetics of the antihistaminic drug diphenhydramine also suggested interethnic variables in the fate of the drug which do not necessarily involve metabolizing capacity. In short, pharmacokinetic factors other than metabolism may make additional contributions to ethnic differences in drug response. Studies of taste and smell are not only models of receptor variability but they may be used to reveal underlying biochemical differences. Furthermore, a polymorphism in tasting ability constituted an epidemiological risk factor for thyroid disease which was greatly enhanced in the presence of an appropriate human leukocyte antigen (HLA, histocompatibility gene). It is clear that the HLA complex will have to be increasingly considered in relation to pharmacological responses. Variabilities of superoxide dismutase and of various enzymes involved in heme production were described briefly because of their inherent or historical interest. In each case, however, the occurrence of variants was confined to small population groups as an expression of founder effects and regional polymorphism. Several other instances of ethnic differences in drug response were merely cited.

Acetylation↗
PubMed1986

Family studies of mephenytoin hydroxylation deficiency.

A genetic polymorphism characterized by deficient drug oxidation exists for the hydroxylation of mephenytoin. This deficiency was first recognized in a family study that suggested an autosomal recessive pattern of inheritance. To confirm the observation, we investigated 28 relatives of five poor metabolizers. Subjects ingested 50 mg of mephenytoin, and the 24-hr urine was analyzed for hydroxymephenytoin. The pedigree data shown here provide strong evidence that deficient mephenytoin hydroxylation is an autosomal recessive trait.

Adolescent↗
PubMed1985

Determination of desferoxamine and a major metabolite by high-performance liquid chromatography. Application to the treatment of aluminium-related disorders.

A high-performance liquid chromatography method is described that permits separation and quantification of desferoxamine, a major metabolite, the iron(III) and the aluminum(III) chelates of desferoxamine. This method now facilitates pharmacokinetic studies on desferoxamine and derivatives designed to study side-effects and metabolite patterns in patients undergoing treatment.

Aluminum↗
PubMed1985

Genetic polymorphism of mephenytoin p(4')-hydroxylation: difference between Orientals and Caucasians.

The genetically controlled mephenytoin p(4')-hydroxylation capacity was determined in 118 Caucasians and 70 Orientals. After an oral dose of 50 or 100 mg of racemic mephenytoin, the amount of p(4')-hydroxymephenytoin in 24 h urine was measured by gas chromatography. Bimodal distribution was found with 9/70 (13%) Orientals and 5/118 (4%) Caucasians demonstrating deficient p(4')-hydroxylation. The statistically significant difference between Orientals and Caucasians (P less than 0.05) was accounted for by the high incidence of poor metabolizers among the Japanese subjects, 7/31 (23%). The frequency among Chinese subjects, 2/39 (5%), was similar to the frequency among Caucasians.

Adolescent↗
PubMed1985

N-Glucosidation of amobarbital in the cat.

N-Glucosidation is a novel pathway of barbiturate metabolism, so far known to occur only in man. A search for an animal model, conducted through in vitro screening, revealed that amobarbital-N-glucoside was formed in liver preparations from the cat. The presence of amobarbital-N-glucoside was demonstrated in cat urine, following i.p. administration of amobarbital.

Amobarbital↗
PubMed1985

Variability of caffeine metabolism in humans.

The metabolic disappearance of caffeine from blood is subject to substantial inter- and intra-individual variation. Smoking of cigarettes and other inducers of aryl hydrocarbon hydroxylase tend to enhance the caffeine metabolism; pregnancy, the use of oral contraceptives, and various kinds of liver disease prolong the caffeine half-life. A genetic component affecting caffeine half-life has not yet been systematically searched for, but might be expected to affect the response to cigarette smoke and similar inducing agents, rather than to provide direct control of caffeine metabolism. The secondary metabolisms of the primary caffeine metabolites are strongly affected by the well-known genetic polymorphism of the N-acetyltransferase of human liver (a polymorphism originally discovered by studies of isoniazid metabolism). Since the proportion of slow acetylators differs in different ethnic populations, many ethnic differences in the ultimate fate of caffeine are to be expected. An observed difference of paraxanthine excretion between Caucasian and Oriental subjects might reflect a difference in the capacity for renal tubular reabsorption of that substance, but further metabolic differences cannot be excluded. The renal elimination of the dimethylxanthines is urinary flow dependent while that of the water soluble metabolites 1-methylxanthine and AFMU (5-acetylamino-6-formylamino-3-methyluracil) is not. Thus, the urinary metabolite pattern can be expected to vary from time to time. However, habitual coffee intake does not affect the metabolite pattern of caffeine.

Acetylation↗