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Biomedical subjects

W Kalow

Publications and source records attributed to W Kalow.

At least 109 records · Page 6Linked to original sources
PubMed1984

High affinity of quinidine for a stereoselective microsomal binding site as determined by a radioreceptor assay.

The techniques of the radioreceptor binding assay were applied to detect stereoselective binding of quinidine and quinine to a site on human liver microsomes. Binding of 3H-dihydroquinidine was 50% inhibited by 20-100 nM quinidine, while its enantiomer quinine did not displace the 3H-ligand at concentrations up to 500 nM. This stereoselectivity agreed with the affinity values measured by functional enzyme assays of cytochrome P450 activity using sparteine or debrisoquine as substrates.

Binding, Competitive↗
PubMed1984

Pharmacoanthropology: outline, problems, and the nature of case histories.

Prerequisites for the evaluation of interethnic differences in response to drugs and toxicants are, first, the understanding of population characteristics in social and genetic terms, and second, the development and use of methods suitable for the pharmacological investigation of fair numbers of subjects. The term pharmacoanthropology is proposed to indicate an appreciation of the difficulties in assessing the causes of quantitative differences between populations, and to emphasize the medical and biological (rather than social or economical) nature of the enquiry. A few case histories are sketched to illustrate the scope of the subject. The classical cases of balanced polymorphism include, for instance, acetylation polymorphism, glucose-6-phosphate dehydrogenase deficiency, and sickle cell anemia. Interethnic differences in alcohol response exemplify a consequence of gross but unexplained differences in gene frequencies for two enzymes, i.e., alcohol and aldehyde dehydrogenases. There may be incidental associations of drug response with blood groups, HLA types, or other traits that differ between populations. Interethnic differences in the predominant nature of essential hypertension appear to illustrate an interaction between diet and genetic constitution, and the resulting patterns of pathology may cause differences in drug response. Clarification of scope and nature of interethnic differences will require many future investigations.

Antipyrine↗
PubMed1984

Pharmacoanthropology: drug metabolism.

This is a report of similarities and differences among various ethnically defined populations with respect to their capacities to metabolize the prototype drugs antipyrine, caffeine, and debrisoquine. There were equal levels of the three main metabolites of antipyrine in the urine of Caucasians and Orientals; differences in antipyrine clearance between English and Indian subjects appeared to have environmental causes. Exploration of various metabolite ratios of caffeine in the urine of Caucasians and Orientals living in Canada showed three patterns: 1) no interethnic difference occurred in the ratio thought to indicate xanthine oxidase activity; 2) products of 7-demethylation and of hydroxylation of paraxanthine , both probably produced by cytochrome P-450, showed different averages in the populations; 3) the new secondary metabolite acetylformyl -methyluracil proved to be a useful indicator of the genetically controlled acetylator status, thereby confirming the well-known population difference for acetylator gene frequency. Analysis of data on debriosquine hydroxylation suggested that interpretation of the standardized metabolic ratio may be appropriate for Caucasian and Oriental groups but is misleading for published data from Saudi Arabia, Nigeria, and Ghana; even these two closely related West African populations seem to differ in debrisoquine metabolism.

Antipyrine↗
PubMed1984

Competitive inhibition of sparteine oxidation in human liver by beta-adrenoceptor antagonists and other cardiovascular drugs.

The rate of oxidation of sparteine by the 9000 x g supernatant fraction of a human liver was measured in the presence of various drugs which exert cardiovascular effects. Hexamethonium, ouabain, caffeine and isoproterenol had no effect on this rate, while alprenolol, metoprolol, oxprenolol, propranolol, timolol, pindolol, lidocaine, mexiletine, 17-n-pentyl-sparteine, tolazoline, quinine, quinidine, cinchonine and cinchonidine inhibited the in vitro reaction competitively. Stereoselective inhibition was observed between quinine (Ki = 15 microM) and quinidine (Ki = 0.06 microM). Genetic evidence suggests that the primary metabolism of sparteine depends on a single species of cytochrome P450. In vitro competitive inhibition of sparteine oxidation by a drug indicates that this drug is capable of occupying the same enzymatic site as sparteine. This may mean that the competing drug is also metabolized at that site and thereby subject to the same genetic variation as sparteine's oxidation; absence of inhibition excludes this possibility.

Adrenergic beta-Agonists↗
PubMed1984

Mephenytoin and sparteine pharmacogenetics in Canadian Caucasians.

The frequency of genetically deficient hydroxylation of mephenytoin (M-defect) was studied in 83 healthy Caucasians living in Toronto. The M-defect was compared with the widely studied genetic polymorphism of sparteine/debrisoquine oxidations (S-defect). After ingestion of mephenytoin and sparteine, urine samples (0 to 24 hr) were analyzed for p(4')-hydroxymephenytoin and urine samples over 0 to 12 hr were analyzed for sparteine and 2-and 5-dehydrosparteine by gas chromatographic methods. Nirvanol, the N-demethylation product of mephenytoin, was determined by a newly developed gas chromatographic/mass spectrometric method. Frequency distributions of both p-hydroxymephenytoin and dehydrosparteine excreted in urine were discontinuous (bimodal), while nirvanol and sparteine data were normally distributed. Two poor metabolizers of mephenytoin excreted 2% to 3% of the dose as p-hydroxymephenytoin and excreted normal amounts of nirvanol, but they were extensive metabolizers of sparteine. Six poor metabolizers of sparteine were found to be extensive metabolizers of mephenytoin (34% to 42% excreted in urine as p-hydroxyme-phenytoin). Thus the M-defect occurs among Canadian Caucasians with a frequency of 2% (0.0% to 7.5% with a confidence limit of 99%) and is independent of the S-defect.

Administration, Oral↗
PubMed1984

Sparteine oxidation by the human liver: absence of inhibition by mephenytoin.

Recent population data suggest independence of the genetic polymorphisms in mephenytoin and sparteine/debrisoquine oxidation. We used human liver preparations to test whether mephenytoin competes with sparteine for binding to the genetically variable cytochrome P-450, which mediates metabolism of both sparteine and debrisoquine. Mephenytoin failed to inhibit in vitro sparteine oxidation. This provides biochemical evidence that the polymorphism of sparteine/debrisoquine metabolism is not related to that of mephenytoin.

Binding, Competitive↗
PubMed1984

A simple test for acetylator phenotype using caffeine.

A method is presented for the use of caffeine, in the forms commonly ingested by a large proportion of the world's population, to test for the clinically important acetylation polymorphism. Each of 146 subjects provided a spot sample of urine between 2 and 6 h after coffee, tea or cola soft drink consumption, and the molar ratio of 5-acetylamino-6- formylamino -3-methyluracil ( AFMU ) to 1-methylxanthine (1X) was determined by a simple h.p.l.c. assay. The ratio afforded segregation of three apparent modes of acetylation capacity in this population, in concordance with a standard sulphamethazine phenotyping procedure and with other methods using controlled caffeine intake and urine collections. The day-to-day consistency of the method was established in eight selected subjects.

Acetylation↗
PubMed1984

A human cytochrome P-450 characterized by inhibition studies as the sparteine-debrisoquine monooxygenase.

The present study compares the debrisoquine monooxygenase and the sparteine monooxygenase activities of human liver microsomes. In the presence of 14 competitive inhibitors, apparent inhibition constants (Ki) as determined by these two activities ranged over four orders of magnitude with a correlation coefficient 0.99. These in vitro results represent the strongest evidence to date that the debrisoquine monooxygenase and the sparteine monooxygenase are identical and involve a single isozyme of cytochrome P-450.

Cytochrome P-450 CYP2D6↗
PubMed1984

Metabolism of 14C-iodochlorhydroxyquin in the dog and the rat.

The disposition and metabolism of iodochlorhydroxyquin (clioquinol), an amebicidal drug with neurotoxic properties, were studied in dogs and rats with 14C-labelled drug. Pharmacokinetic studies in the dog demonstrated that the compound was well absorbed; the bioavailability was 36% of the dose of 1 mg/kg. The serum half-life was 1.3-1.8 h. In both the dog and the rat, biliary excretion was a major route of elimination. The dog excreted 27% of an intravenously administered dose (1 mg/kg) in the bile within 2 h; the rat excreted 39% of the dose (5 mg/kg i.v.) in less than 3 h. Elimination via the renal route was also substantial in both species. Urinary and biliary metabolites were separated by TLC (thin layer chromatography) and identified as sulfate and glucuronide conjugates in both species. No evidence for any other metabolites was found. A significant difference was observed between the dog and the rat in the extent of conjugation; the percentage radioactivity in the urine accounted for by the unchanged compound was six to twenty times greater for the dog than for the rat. The species differences in the disposition and metabolism of the compound might explain its greater toxicity in the dog than in the rat.

Administration, Oral↗
PubMed1983

Inhibition of sparteine oxidation in human liver by tricyclic antidepressants and other drugs.

Testing for competitive inhibition of sparteine oxidation in the 9000 x g supernatant fraction from human liver provides an in vitro means to identify drugs which can bind to the same form of cytochrome P450 which oxidizes sparteine. There has so far been only two outcomes of this test: either the drug examined competed with sparteine for a common binding site, or it did not inhibit the reaction. The results of such in vitro testing implicated the involvement of guanoxan, nortriptyline, desipramine, imipramine, amitriptyline and chlorpromazine with this enzyme. Amobarbital, tolbutamide and guanethidine in therapeutic concentrations did not interfere with sparteine oxidation by this preparation.

Antidepressive Agents, Tricyclic↗
PubMed1983

Variation in amobarbital metabolism: evaluation of a simplified population study.

Kinetic constants of amobarbital metabolism were established for 52 subjects on the basis of urinary analysis extending over several days, usually 96 hr. There was no evidence of effect of age or sex on any of the constants. C-Hydroxylation was induced by cigarette smoking as much as 100%, but glucosidation was not affected. A factor influencing the constants was ethnicity of subjects (Caucasian or Oriental). This study confirms ethnic differences in amobarbital metabolism that were reported after measuring the concentration of metabolites in single samples of urine, that is, urine specimens voided during the postdistributive phase after oral drug intake. It appears that extreme simplification of sampling methods may be contemplated in the design of metabolic investigations of populations.

Adult↗
PubMed1983

Polymorphic N-acetylation of a caffeine metabolite.

In the course of investigations into variability in the metabolism of caffeine in human populations, urinary levels of 5-acetylamino-6-formylamino-3-methyluracil (AFMU), a newly discovered ring-opened metabolite of caffeine, were found to be both bimodally distributed and interethnically variable in samples (Caucasian: n = 42; Oriental: n = 26) from the Toronto population. To test the premise that the polymorphic N-acetyltransferase enzyme (E.C.2.3.1.5) could be responsible for the production of AFMU, 20 of the subjects were phenotyped for acetylator status using sulfamethazine (SMZ). Concordance for all subjects between AFMU production and SMZ acetylation strongly suggests that the acetylation polymorphism is involved in the formation of AFMU in man.

Acetylation↗
PubMed1983

Comparative pharmacogenetics of sparteine and debrisoquine.

Capacities to oxidize sparteine and debrisoquine in healthy Canadian Caucasians were compared. The Spearman rank correlation between the conventional urinary metabolic ratios (drug/metabolite) was rs = 0.79 (P less than 0.001), but the sparteine metabolic ratio appears to be the more discriminating probe to distinguish metabolizers and nonmetabolizers. The urinary amount of oxidized sparteine alone may allow reliable detection of nonmetabolizers. From a total of 17 poor metabolizers observed in this study and in studies in Germany and Sweden, all were deficient in metabolizing capacity for both sparteine and debrisoquine.

Chromatography, Gas↗
PubMed1983

Variability in caffeine metabolism.

Urinary metabolites excreted after oral caffeine were quantified in a healthy sample (n = 68) from the Toronto population by HPLC analyses. The profile of metabolites, assessed by examining particular metabolite ratios, was found to differ widely among subjects. Ratios denoting cytochrome P-450-dependent activities were shown to be interethnically variable between oriental and Caucasian groups, whereas those indicative of xanthine oxidase activity exhibited neither significant interindividual variation nor an ethnic difference. It was also shown that a ratio providing an index of polymorphic N-acetyltransferase activity holds promise as a simple marker for acetylator status in man.

Acetyltransferases↗
PubMed1983

The occurrence of two hepatic microsomal sites for amobarbital hydroxylation.

Amobarbital metabolism in human liver and in rat liver, lung, kidney, and small intestine was measured in vitro using thin-layer chromatography (TLC) for separation of metabolites generated from incubation with [2-14C]amobarbital. Formation of 3'-hydroxyamobarbital (C-OH) occurred primarily in the liver. The kinetics of C-OH formation by rat liver microsomes or isolated hepatocytes could be described by a Michaelis-Menten model incorporating two metabolic sites, one characterized by high-affinity and low-velocity constants (Km = 0.054 +/- 0.012 mM, Vmax = 16.89 +/- 4.27 nmol C-OH x g liver-1 x min-1), the other by low-affinity and high-velocity (Km = 0.679 +/- 0.097 mM, Vmax = 66.0 +/- 5.41 nmol C-OH x g liver-1 x min-1). The kinetic parameters of the high-affinity site differed significantly between whole cells and homogenates. Pretreatment with phenobarbital for 3 days induced only the high-affinity site. Quantitation of C-OH formation in four human liver samples from several sources showed that metabolism may conform to the two-site model observed in rat liver.

Amobarbital↗
PubMed1983

Paraoxonase phenotype distribution in Canadian Indian and Inuit populations.

Test objects were the sera of 57 North American Indian and 67 Inuit subjects. The paraoxon-hydrolyzing activity, a, was determined, as well as the paraoxonase-phenotyping ratio, c/b, a ratio designating enzyme activation by Na+ in the presence of Ca2+. The values of c/b were clearly bimodally distributed. Location of the modes and of the antimodal gap were in perfect agreement with the results previously obtained on Caucasian sera. This allowed us to retain the criterion which had been already established in the study of Caucasians, i.e., c/b less than 1.5 = "low-activity" phenotype, and c/b greater than 1.5 = "high-activity" phenotype. The proportions of individuals in each mode differed, however. In Caucasians, the frequency of the "low-activity" phenotype had been estimated as 51.2%. In Indians and Inuits, it was 7.0% and 6.0%, respectively. Independent of phenotype, Indian and Inuit sera displayed lower paraoxon-hydrolyzing activity than did Caucasian sera.

Aryldialkylphosphatase↗
PubMed1983

The fate of orally administered [4-14C]phenytoin in two healthy male volunteers.

A recovery study was conducted to determine whether phenytoin (DPH), like the barbiturates, is metabolized via the recently discovered N-glucosidation pathway. Virtually 100% of the ingested 14C-labelled doses in two subjects could be accounted for in the excreta within 5 days, with 35% in feces and 65% in urine. Radioactivity in the urine was entirely due to free and conjugated 5-(4-hydroxy-phenyl)-5-phenylhydantoin (p-HPPH) and the dihydrodiol, and that in the feces mostly due to the unmetabolized drug. There was no indication of phenytoin N-glucoside being excreted in either the urine or feces of either subject, although one of the subjects was known to possess a particularly strong N-glucosidation capacity for barbiturates. The other subject was a poor metabolizer of debrisoquine and sparteine. Nevertheless, the DPH disappearance from serum and the DPH metabolite excretion in urine were virtually alike in these two subjects, indicating that the debrisoquine 4-hydroxylating and DPH hydroxylating capacities may be separable entities.

Administration, Oral↗