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Biomedical subjects

A Küpfer

Publications and source records attributed to A Küpfer.

At least 55 records · Page 3Linked to original sources
PubMed1984

Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man.

Inherited deficiency in mephenytoin hydroxylation was observed in a family study. It is important that the propositus was of the extensive metabolizer phenotype for the genetically controlled hydroxylation of debrisoquine. Thus, a genetic polymorphism of drug hydroxylation was suspected for mephenytoin. A population study of mephenytoin hydroxylation, combined with identification of extensive and poor debrisoquine hydroxylation phenotypes, was carried out in 221 unrelated normal volunteers. Twelve of them (5%) exhibited defective aromatic hydroxylation of mephenytoin, and 23 (10%) could be identified as poor metabolizers of debrisoquine. Amongst these 35 subjects with a drug hydroxylation deficiency, 3 (or 0.5%; 1 female, 2 males) displayed both defects simultaneously. A panel study of 10 extensive and 10 poor metabolizers of mephenytoin showed that the ability to perform aromatic hydroxylation of the demethylated mephenytoin metabolite nirvanol (5-phenyl-5-ethylhydantoin) was co-inherited with the mephenytoin hydroxylation polymorphism. Family studies suggested that poor metabolizer phenotypes of nirvanol and mephenytoin were most likely to have the homozygous genotype for an autosomal recessive allele of deficient aromatic drug hydroxylation. Intra-subject comparison of the debrisoquine and mephenytoin hydroxylation phenotypes in these subjects indicated that deficiency in the two drug hydroxylations occurred independently. Consequently, the co-inheritance of extensive and poor hydroxylation of mephenytoin and nirvanol, respectively, represents a new drug hydroxylation polymorphism in man.

Adult↗
PubMed1984

Mephenytoin hydroxylation deficiency: kinetics after repeated doses.

Deficient aromatic hydroxylation of S-mephenytoin was observed in an index subject during a kinetic study of stereoselective metabolism of mephenytoin. A genetic basis for this defect was suggested by decreased urinary recovery of 3-methyl-5-(4-hydroxyphenyl)-5-ethylhydantoin (4-OH-M) in the 24 hr after oral racemic mephenytoin in two brothers of the propositus. The parents and a third brother had urinary recoveries of 4-OH-M of the same order as in a group of 20 normal subjects. The kinetic implications of this defect were studied in the index subject and compared with four normal subjects after a single oral dose of differentially radiolabeled pseudoracemic mephenytoin (5 microCi of 14C-S-mephenytoin, 45 microCi of H3-R-mephenytoin, and 11.5 mumol/kg of both S- and R-mephenytoin) followed by single oral doses of 1.4 mmol of unlabeled racemic mephenytoin daily the next 4 days. In normal subjects, there was substrate stereoselective metabolism with the S-enantiomer rapidly excreted as 4-OH-M and the R-enantiomer slowly excreted as 5-phenyl-5-ethylhydantoin (PEH). Stereoselective metabolism persisted during repeated dosing. In the hydroxylation-deficient subject, there was no evidence of stereoselective metabolism, recovery of 4-OH-M was low, and both enantiomers were slowly excreted, predominantly as PEH. Plasma PEH concentrations and urinary PEH excretion rates were approximately twice that in normal subjects. Thus a genetic deficiency in ability to hydroxylate S-mephenytoin results in the S-enantiomer metabolization by the alternate route of demethylation to PEH that cumulates, thereby, in comparison to the normal, effectively doubling the dose of total hydantoin.

Adult↗
PubMed1984

Urinary bile acid and bile alcohol excretion does not reflect the genetic polymorphism of debrisoquine hydroxylation.

Excretion of the major urinary bile alcohol 27-nor-5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24,25- pentol , and of cholic, chenodeoxycholic, deoxycholic and lithocholic acid was measured in 24 h urine collections of 10 extensive and seven poor metabolizers of debrisoquine. There was no significant difference of the excretion of these cholesterol metabolites between the two groups, indicating that cholesterol hydroxylation to bile alcohols and bile acids is probably not controlled by the same genes responsible for the 'debrisoquine-type' hydroxylation polymorphism.

Adult↗
PubMed1984

Stereoselectivity of the arene epoxide pathway of mephenytoin hydroxylation in man.

Stereoselective metabolism of mephenytoin has been investigated in four normal subjects by comparing urinary recoveries of hydroxylated metabolites after administration of racemic RS-mephenytoin (1.4 mmol/day) and R-mephenytoin (0.7 mmol/day) on separate occasions. Gas chromatography-mass spectrometry was employed to measure the urinary recovery of 3-methyl-5-(4-hydroxyphenyl)-5-ethylhydantoin (4-OH-M) and mephenytoin catechol, methylcatechol, and dihydrodiol metabolites. Following a single oral dose of racemic mephenytoin, 4-OH-M, mephenytoin catechol, and methylcatechol metabolites were identified in urine mainly as conjugates, whereas the dihydrodiol metabolite was recovered mainly in its unconjugated form. Urinary elimination of each metabolite was similar on days 1 and 10 of chronic racemic mephenytoin administration. Following R-mephenytoin administration, urinary recoveries of hydroxylated metabolites were five to 10 times smaller than after administration of the racemic drug. This implies substrate-stereoselective hydroxylation of the S-enantiomer of mephenytoin. In one subject with a genetic deficiency of aromatic mephenytoin hydroxylation deficiency, the excretion of each hydroxylated mephenytoin metabolite after RS-mephenytoin administration was decreased to 5-15% of the values found in the four extensively hydroxylating study volunteers. The impaired formation of hydroxylated mephenytoin metabolites in genetic hydroxylation deficiency, in conjunction with stereoselective hydroxylation of S-mephenytoin via an extensive NIH shift in normal man, is consistent with the hypothesis that the formation of the S-mephenytoin arene oxide is under genetic control and represents the initial enzymatic reaction of stereoselective aromatic mephenytoin hydroxylation. The formation of this potentially reactive metabolite of S-mephenytoin may have implications in mephenytoin-induced toxicity.

Ethers, Cyclic↗
PubMed1984

Stereoselective metabolism and pharmacogenetic control of 5-phenyl-5-ethylhydantoin (nirvanol) in humans.

Aromatic hydroxylation of 5-phenyl-5-ethylhydantoin (PEH) has been investigated in humans. Single oral doses of S-PEH (247 mumol) were given to seven extensive and seven poor hydroxylators of mephenytoin. Urinary recovery of PEH and 5-(4-hydroxyphenyl)-5-ethylhydantoin (4-OH-PEH) indicated that all extensive metabolizer subjects excreted appreciable quantities of 4-OH-PEH, whereas all poor metabolizer subjects had only trace amounts of 4-OH-PEH in their urine. Four extensive metabolizer subjects received dual radiolabeled (S-[14C]PEH, R-[3H]PEH) pseudoracemic (494 mumol R-PEH, 494 mumol S-PEH) PEH and had serial urine and blood samples collected over 16 days. The urinary excretion rates of S-PEH and S-4-OH-PEH had half-lives of approximately 4.5 days whereas those of R-PEH and R-4-OH-PEH were approximately 10 days. The initial S/R ratio of 4-OH-PEH in urine was 14:1 whereas that of PEH was 1:1. Stereoselective hydroxylation in these four subjects was confirmed by the negligible recovery of 4-OH-PEH after oral administration of R-PEH (494 mumol). After racemic administration, the sum of S-and R-PEH plasma concentrations declined biexponentially with half-lives of the alpha- and beta-phases being consistent with the total plasma concentration reflecting the sum of the different rates of elimination of the two enantiomers. These results are consistent with the hypothesis that the same drug metabolizing enzymes are involved in the aromatic hydroxylation of S-mephenytoin and S-PEH.

Adolescent↗
PubMed1983

Contribution of the genetic status of oxidative metabolism to variability in the plasma concentrations of beta-adrenoceptor blocking agents.

The oxidative metabolism of bufuralol is under the same genetic control as that of debrisoquine and sparteine. 154 fasting volunteers received a 30 mg tablet of bufuralol and a blood sample was taken 3 h later. In poor metabolizers (8% of the sample) the plasma bufuralol concentrations were very high and the metabolite concentrations were low. The genetic oxidative status is a major source of interindividual variation in the plasma concentration of drugs that undergo oxidative metabolism.

Adrenergic beta-Antagonists↗
PubMed1982

Spectral binding studies of the polymorphically metabolized drugs debrisoquine, sparteine and phenformin by cytochrome P-450 of normal and hydroxylation deficient rat strains.

The mechanisms of polymorphic drug hydroxylation of debrisoquine, sparteine and related drugs in vivo have been investigated using Cyt P-450 preparations of inbred rat strains as an in vitro model of the poor and extensive metabolizer phenotypes found in various rat strains and in man. Optical difference spectroscopy with debrisoquine, sparteine, phenformin and three other drugs (selected test compounds with proven or suspected hydroxylation polymorphisms in man) exhibited Type 1 binding in normal Sprague-Dawley, Fischer and Lewis Cyt P-450, whereas no Type I drug binding was found in the hydroxylation deficient DA rat liver Cyt P-450. Cyt P-450 content and Type II drug binding of metiamide was the same in normal and hydroxylation deficient rat liver microsomes. The pronounced Type I drug binding in extensive hydroxylation Cyt P-450 and the defective Type I binding in DA Cyt P-450 in vitro, therefore, closely parallels the polymorphic hydroxylation pattern of these test drugs found in the four rat strains studied in vivo. Consequently, missing binding properties of Cyt P-450 or of its micro-environment might represent the enzymatic defect underlying the genetically determined hydroxylation deficiency of polymorphically metabolized drugs in the poor metabolizer phenotype in the DA rat and, by inference, in man.

Animals↗
PubMed1982

Analysis of hydroxylated and demethylated metabolites of mephenytoin in man and laboratory animals using gas-liquid chromatography and high-performance liquid chromatography.

Separation of urinary mephenytoin metabolites was evaluated under various gas-liquid chromatographic (GLC) and high-performance liquid chromatographic (HPLC) conditions. A simple and rapid alkylation procedure is described for GLC-using a nitrogen sensitive thermionic detector. The in situ formation of sodium methinylsulfinylmethide is used as base for the perpropylation of hydantoins and their metabolites. Normal-and reversed-phase HPLC of the underivatized compounds was performed using four different types of stationary phases. None of the GLC systems separated all the six hydantoin compounds tested, whereas, normal-and reversed-phase HPLC were able to obtain a complete separation of these compounds. The major metabolites of mephenytoin were 5-phenyl-5-ethylhydantoin, 3-methyl-5-(4-hydroxyphenyl)-5-ethylhydantoin and 5-(4-hydroxyphenyl)-5-ethylhydantoin in man, rat, mouse, rabbit, and guinea pig. 3-Methyl-5-phenyl-5-(2-hydroxyethyl)-hydantoin and 3-methyl-5-(3-hydroxyphenyl)-5-ethylhydantoin are major metabolites in the dog.

Animals↗
PubMed1982

[Drug hydroxylation disorders (debrisoquin type) in a random sample of the Swiss population].

The hydroxylation phenotype was determined in a sample of the Swiss population consisting of 222 normal unrelated subjects (131 women, 91 men). Following oral administration of a single dose of 19 mg debrisoquine, urine was collected for 8 hours. Urinary concentrations of parent compound and its major metabolite (4-hydroxydebrisoquine) were measured with GLC and their molar ratio ("metabolic ratio", MR) was calculated and plotted as a frequency distribution histogram. The frequency distribution of the MR was clearly bimodal, exhibiting two clusters of MR's of 0.1 to 1.0 and 20 to 100, respectively. Using probit analysis, the antimode was found at an MR of 12.6 Consequently, 22 subjects (16 women, 6 men), representing 10% of the population studied, were, with an MR of greater than 12.6, considered to be poor hydroxylators (PM). The families of two subjects, established as PMs in the population study, were also investigated. One family was found to be the first known pairing of homozygous PM parents with all 6 offspring exhibiting the PM phenotype. In both families the pattern was consistent with an autosomal recessive mode of inheritance for the two alleles E (extensive) and N (none) respectively. Clinical consequences of the PM phenotype known to date are summarized. Since some drugs typically used for longterm treatment (such as perhexiline, phenytoin, nortriptyline, guanoxan) are subject to the same hydroxylation pathway, PM patients are likely to be at higher risk of drug toxicity. This relationship has been well documented for perhexiline-induced neuropathy. Conversely, it is conceivable that with the use of prodrugs which have to be hydroxylated to the active compound, PM subjects might turn out to be "non-responders".

Adolescent↗
PubMed1982

Relation of in vivo drug metabolism to stereoselective fetal hydantoin toxicology in mouse: evaluation of mephenytoin and its metabolite, nirvanol.

Anticonvulsant therapy during pregnancy with the hydantoin phenytoin carries a risk of teratologic sequelae and developmental retardation known as the fetal hydantoin syndrome. The putative teratogen is a highly reactive arene oxide intermediate produced during phenytoin metabolism. By using two structurally similar hydantoins, mephenytoin and its in vivo demethylated metabolite nirvanol, we examined the possibility for a stereoselective dissociation of fetal hydantoin toxicity from maternal anticonvulsant activity. The d-isomers (S-enantiomers) of mephenytoin and nirvanol are p-hydroxylated via an arene oxide and hence were suspect teratogens. The l-isomers (R-enantiomers), being eliminated primarily via alternate pathways, were expected to be less toxic. Equimolar doses of the d- or l-isomers of mephenytoin or nirvanol were administered to pregnant Swiss ICR mice i.p. on gestational day 10. An 8-fold increase in fetal resorptions and a significant 11% decrease in fetal body weight was observed in the group treated with l-nirvanol, whereas no or minimal toxicity was observed in the other treatment groups. The blood clearance for d-nirvanol was double that for l-nirvanol, with correspondingly higher urinary concentrations of arene oxide-mediated metabolites. ANIH shift during metabolism supported the presence of an arene oxide intermediate. Contrary to our expectations, only l-nirvanol, the isomer producing less arene oxide, demonstrated fetal toxicity, thus raising some doubt concerning the arene oxide as the putative hydantoin teratogen. Further animal studies with the d-isomers of mephenytoin and nirvanol may lead to an anticonvulsant of choice during pregnancy.

Animals↗
PubMed1981

Phenytoin therapy for epileptic children: evaluation of salivary and plasma concentrations and of methods of assessing compliance.

Monitoring phenytoin therapy in children is difficult because they fear blood sampling, yet frequent control of phenytoin levels may be necessary because of the age-dependence of phenytoin metabolism. In 22 patients aged between six and 15 years, phenytoin concentrations were studied in mixed saliva and parotid saliva and were compared with plasma levels from blood obtained at the same time. For mixed saliva, the saliva: plasma concentration ratio was 0.11 +/- SD 0.04 and in parotid saliva it was 0.10 +/- 0.06. In addition, compliance was studied in 13 children, each receiving between three and seven different quantities of phenytoin. Clinical judgement about compliance agreed well with the two laboratory measures. A graphic analysis of the relationship between plasma concentration and dosage is proposed as practical method of assessing compliance, because it appears to be both simple and reliable, and therefore suitable for routine use.

Adolescent↗
PubMed1981

The differential localization of various drug metabolizing systems within the rat liver lobule as determined by the hepatotoxins allyl alcohol, carbon tetrachloride and bromobenzene.

Rats were pretreated with allyl alcohol, carbon tetrachloride or bromobenzene to induce histopathological evidence of periportal, midzonal to centrilobular, and centrilobular hepatic necrosis. The amount of various drug metabolizing enzyme systems present after necrosis was determined indirectly by measuring the rate of metabolism for specific substrates in vitro. The chemically induced hepatocellular injury of these toxins produced variable but significant alterations in hepatic drug metabolism. The changes in enzymatic activity related well with the area of the lesion produced by each toxin. Thus, these hepatotoxins appear to be useful as probes to determine the hepatolobular distribution of the various drug metabolizing enzyme systems studied. Aniline hydroxylase and p-nitroanisole o-demethylase were concentrated in the midzonal and periportal zones, while aminopyrine N-demethylase was more uniformly distributed along the cytochrome P-450 gradient. Glucuronyltransferase was more heavily concentrated in the periportal-midzonal area, acetyltransferase was centrilobular-midzonal and glutathionetransferase was concentrated in the midzonal region. Thus, as is the case for cytochrome P-450, there appears to be a high degree of regional organization for all of the drug metabolizing enzymes within the hepatic lobule.

1-Propanol↗