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M Eichelbaum

Publications and source records attributed to M Eichelbaum.

At least 163 records · Page 9Linked to original sources
PubMed1988

Further analysis of sparteine oxidation in a Japanese population and comparison with data observed in different ethnic populations.

1. Data on the oxidation polymorphism of sparteine (SP) studied in 84 unrelated Japanese subjects of whom two (2.4%) were classified as poor metabolizers (PMs) were re-evaluated. The data were obtained from 6-hour urinary excretion ratios of SP to 2- and 5-dehydrosparteines (DHS), after an oral dose of 100 mg of SP sulphate. 2. Urinary excretion of both SP and DHS correlated with the SP/DHS ratio (rs = 0.862 and -0.756, respectively, P less than 0.001). In addition, urinary excretion of 2-DHS, 5-DHS or total DHS discriminated between PMs and extensive metabolizers (EMs). There was also a highly significant correlation (rs = 0.669, P less than 0.001) between the urinary excretion of 2- and 5-DHS. 3. These re-evaluated results on the oxidation polymorphism of SP indicate that 2- and 5-DHS formation from SP shares a common metabolic pathway (presumably via the same P-450 isozyme), and that the SP/DHS ratio, conventionally used as a discriminating index between PMs and EMs, quantitatively reflects the capacity of 2- and 5-DHS formation. 4. The benefit of using a shorter (6 h) collection period for assessing the individual oxidation phenotype of SP and inter-ethnic comparison of SP oxidation is also discussed.

Adult↗
PubMed1988

Investigations on the intraindividual constancy of the ratio of carbamazepine to carbamazepine-10,11-epoxide in man.

The constancy of the ratio of carbamazepine (5H-dibenzo[b,f]azepine-5-carboxamide) to carbamazepine-10,11-epoxide was investigated in epileptic patients receiving carbamazepine (Tegretal) monotherapy. We observed a significant interindividual difference, but not between the times in a single patient. Together with the similarly evaluated concordance coefficient, this indicates a certain intraindividual constancy of the ratio between carbamazepine and its epoxide. The carbamazepine:carbamazepine epoxide ratio was dose-dependent, while a sex difference could not be demonstrated.

Adolescent↗
PubMed1987

Severe complications of antianginal drug therapy in a patient identified as a poor metabolizer of metoprolol, propafenone, diltiazem, and sparteine.

A 47-year-old patient suffering from coronary artery disease was admitted to the CCU in shock with III. AV block, severe hypotension, and impairment of ventricular function. One week prior to admission a therapy with standard doses of metoprolol (100 mg t.i.d. and then 100 mg b.i.d.) had been initiated. Two days before admission diltiazem (60 mg b.i.d.) was prescribed in addition. Analyses of a blood sample revealed unusually high plasma concentrations of metoprolol (greater than 3000 ng/ml) and diltiazem (526 ng/ml). The patient recovered within 1 week following discontinuation of antianginal therapy. Three months later the patient was exposed to a single dose of metoprolol, diltiazem, propafenone (since he had received this drug in the past), and sparteine (as a probe for the debrisoquine/sparteine type polymorphism of oxidative drug metabolism). It was found that he was a poor metabolizer of all four drugs, indicating that their metabolism is under the same genetic control. Therefore, patients belonging to the poor-metabolizer phenotype of sparteine/debrisoquine polymorphism in drug metabolism, which constitutes 6.4% of the German population, may experience adverse drug reactions when treated with standard doses of one of these drugs alone. Moreover, the coadministration of these frequently used drugs is expected to be especially harmful in this subgroup of patients.

Angina Pectoris↗
PubMed1987

Enzymatic basis of the debrisoquine/sparteine-type genetic polymorphism of drug oxidation. Characterization of bufuralol 1'-hydroxylation in liver microsomes of in vivo phenotyped carriers of the genetic deficiency.

The genetically controlled polymorphic oxidation of debrisoquine and sparteine is caused by the absence or functional deficiency of a cytochrome P-450 isozyme. In order to elucidate the mechanisms underlying the differences in cytochrome P-450 function we have studied the 1'-hydroxylation of the prototype drug bufuralol in human liver microsomes of individuals phenotyped in vivo as extensive metabolizers (EM, N = 10), poor metabolizers (PM, N = 5) and in subjects with an intermediate rate of metabolism (IM, N = 4). PM- as compared to EM-microsomes were characterized by a decreased Vmax for (+)-bufuralol 1'-hydroxylation (7.51 +/- 2.03 nmol X mg-1 X hr-1 vs 11.95 +/- 4.80 nmol X mg-1 X hr-1) but not for (-)-bufuralol 1'-hydroxylation (4.72 +/- 0.87 nmol X mg-1 X hr-1 vs 5.55 +/- 1.49 nmol X mg-1 X hr-1). The apparent Km for (+)-bufuralol 1'-hydroxylation was increased in PM microsomes (118 +/- 84.9 microM vs 17.9 +/- 6.30 microM). Inhibition of bufuralol 1'-hydroxylation by quinidine was biphasic in EM microsomes, providing further support for the involvement of at least two cytochrome P-450 isozymes. Quinidine acted as a competitive inhibitor of only the high affinity/stereoselectivity component of the reaction. Our data suggest that the debrisoquine/sparteine type of oxidation polymorphism is caused by an almost complete loss of a minor cytochrome P-450 isozyme which has a high affinity and stereoselectivity for (+)-bufuralol and a high sensitivity to inhibition by quinidine.

Adult↗
PubMed1987

Evidence for altered catalytic properties of the cytochrome P-450 involved in sparteine oxidation in poor metabolizers.

Sparteine metabolism was studied in human liver microsomes from nine extensive ([EM] urinary metabolic ratio [MR] less than 20) and four poor metabolizers ([PM] MR greater than 20). The formation of 2- and 5-dehydrospartein displayed monophasic Michaelis-Menten kinetics. In livers from PMs the formation of the major sparteine metabolite 2-dehydrosparteine was characterized by more than a thirtyfold increase in Michaelis-Menten constant (Km)(1880 +/- 1044 mumol/L) as compared with EM subjects with an MR less than 1 (58.3 +/- 38.8 mumol/L). EM subjects with an MR greater than 3 who may constitute heterozygous metabolizers showed Km values in between (658 +/- 301 mumol/L). There was no difference in maximum rate of metabolism (Vmax) of 2-dehydrosparteine formation between EM and PM subjects (101 +/- 39 vs. 86 +/- 52 pmol/min/mg). The formation of 5-dehydrosparteine exhibited a Km of 100 +/- 123 mumol/L similar to the Km of 2-dehydrosparteine formation. The urinary MR correlated positively with the Km for 2-dehydrosparteine formation. The intrinsic clearance for 2-dehydrosparteine showed a highly significant negative correlation with the MR. The pronounced differences in Km together with the significant correlation between Km and MR with no marked differences in Vmax between phenotypes suggest that the impaired oxidation capacity in PM subjects is more likely the result of a P-450 isozyme with altered catalytic properties rather than a decreased amount of enzyme.

Adult↗
PubMed1987

Chromosomal assignment of human cytochrome P-450 (debrisoquine/sparteine type) to chromosome 22.

In order to determine on which chromosome the gene controlling human cytochrome P-450 (debrisoquine/sparteine type) is located a linkage study of polymorphic sparteine oxidation (PSO) to various polymorphic markers was carried out. Positive information for linkage between PSO and the P1 blood group was obtained with a maximal LOD-score of LOD = 3.35 for both male and female recombination fraction estimates of theta m = theta f = 0.0. The P1 blood group has been recently mapped to the long arm of chromosome 22. Thus it can be concluded that the gene controlling human cytochrome P-450 (debrisoquine/sparteine) is situated on the long arm of chromosome 22 in close vicinity to P1.

Alleles↗
PubMed1987

Evidence for polymorphic oxidation of sparteine in Japanese subjects.

The metabolism of sparteine which exhibits a genetic polymorphism in Caucasians was studied in 84 unrelated Japanese subjects. In contrast to a recent study where debrisoquine was used as a probe and no poor metabolizers could be observed in Japanese involving 100 subjects, two subjects had a urinary metabolic ratio of sparteine greater than 20 and thus were poor metabolizers of sparteine. The incidence of poor metabolizer phenotype of sparteine oxidation of 2% seems to be lower in Japanese as compared with various Caucasian populations where 5 to 10% are poor metabolizers of sparteine. However, this is not conclusive, because the 95% confidence interval of the observed frequency, 0.6 to 8%, covers the range reported in the literature for Caucasians.

Adult↗
PubMed1987

Application of stable isotope methodology to study the pharmacokinetics, bioavailability and metabolism of nitrendipine after i.v. and p.o. administration.

1. The pharmacokinetics, bioavailability and metabolism of nitrendipine were studied in six healthy volunteers (three females, three males) using [13C4]-nitrendipine as a biological internal standard. In the first study the drug was administered simultaneously by the i.v. [13C4] and p.o. (solution) routes and in a second study two oral preparations (13C4-solution and commercial tablet) were administered, also simultaneously. 2. The mean terminal elimination half-life was 8.3 +/- 3.2 h (range 3.4 to 16 h) with no differences between the intravenous and oral route of administration. Total plasma clearance averaged 18.7 +/- 0.6 ml min-1 kg-1 and volume of distribution at steady state 5.4 +/- 2.4 1 kg-1. 3. Following oral administration of nitrendipine solution the percentage of dose absorbed was 88.4 +/- 16.0% based on urinary excretion of metabolites. Despite its almost complete absorption, absolute bioavailability of the solution was only 22.6 +/- 6.7% due to extensive presystemic elimination. The bioavailability of the commercial tablet relative to the solution was 82.2 +/- 20.3%. 4. Both after i.v. and oral administration the drug was extensively metabolized with less than 0.5% of the dose excreted as unchanged drug in urine. Cleavage of the two ester functions in position 3 and 5, respectively, to carboxylic acids and further hydroxylation of the methyl groups in position 2 and 6 of the pyridine ring to the corresponding hydroxymethyl carboxylic acids constituted the major urinary metabolites accounting for 35.0 +/- 16.5% (i.v.) and 32.8 +/- 20.4% (p.o.), respectively, of the dose administered. 5. Binding of nitrendipine to plasma proteins was high with a fraction unbound of only 0.02 +/- 0.012 (range 0.011 to 0.036).

Administration, Oral↗
PubMed1986

A sensitive capillary GC assay for the determination of sparteine oxidation products in microsomal fractions of human liver.

A sensitive method for the assay of sparteine oxidase activity in vitro by microsomal fractions of human liver is described. The activity of sparteine oxidase was assessed by the formation of 2- and 5-dehydrosparteines, which were estimated by capillary gas chromatography with N2-FID detection. The limit of detection of the two metabolites, 2- and 5-dehydrosparteine, was 10 pmol (2.3 ng) per sample. Sparteine oxidase activity was linear with microsomal protein concentration ranging from 25 to 200 ug and with incubation times between 5 and 60 minutes. Omission of NADPH on incubation under an atmosphere of carbon monoxide inhibited formation of both metabolites, thus indicating that aforementioned metabolites arise in reaction catalyzed by cytochrome P-450. In three liver samples from humans classified as extensive (EM) metabolizers the formation of 2- and 5-dehydrosparteines was observed, 2-dehydrosparteine being the major metabolite. In these samples sparteine oxidase activity was characterised by Vmax = 136 +/- 53 pmol/min/mg and Km = 44 +/- 12 microM for 2-dehydrosparteine formation. For 5-dehydrosparteine formation the following values were obtained: Vmax = 57 +/- 18 pmol/min/mg and Km = 42 +/- 26 microM. In a liver sample from a poor metabolizer (PM) only the formation of 2-dehydrosparteine was detected with the method of analysis used. In this sample a great increase in Km (Km PM = 3033 microM) was noted, while Vmax was very similar to those obtained for 2-dehydrosparteine formation in EM subjects (Vmax PM = 147 pmol min/mg).

Chromatography, Gas↗
PubMed1986

Quantification of nitrendipine by stable isotope dilution and electron-capture negative ion chemical ionization.

The electron-capture properties of nitrendipine, a 1,4-dihydro-pyridine derivative with antihypertensive activity, have been applied to develop a sensitive and specific assay in biological fluids using capillary column gas chromatography and measurement in negative ion chemical ionization mode. The synthesis of a 13C4-labelled analogue suitable as a biological internal standard for bioavailability studies and of a 2H8-labelled analogue, which serves as internal standard, is described. The electron-capture positive ion chemical ionization and electron-capture negative ion chemical ionization mass spectra of nitrendipine and its isotope-labelled analogues are compared. The assay has a detection limit of 100 pg ml-1 plasma with a coefficient of variation of 10.2% using the selected ion monitoring mode and electron-capture negative ion chemical ionization. The method is specific, sensitive and accurate to determine terminal half-life times after intravenous and oral administration of nitrendipine and its 13C-analogue. From the nearly identical plasma concentration-time profile of nitrendipine and its 13C-labelled analogue, an isotopic effect can be excluded. Thus, the synthesized 13C4-analogue should be well suited as a biological standard for bioavailability studies.

Adult↗
PubMed1986

Pharmacokinetics and metabolism of quinidine in extensive and poor metabolisers of sparteine.

The pharmacokinetics and metabolism of quinidine were investigated in extensive and poor metabolisers of sparteine. No differences in plasma clearance, terminal half life, volume of distribution or cumulative urinary excretion of quinidine, 3-hydroxyquinidine and quinidine-N-oxide were observed between phenotypes. Thus, it is unlikely that quinidine metabolism is controlled by the sparteine/debrisoquine gene locus.

Adult↗
PubMed1986

The influence of enzyme induction on polymorphic sparteine oxidation.

The effects of antipyrine (1200 mg day-1), phenobarbitone (100 mg day-1) and rifampicin (600 mg and 1200 mg day-1, respectively) administration for 7 days on sparteine metabolism and 6 beta-hydroxycortisol excretion were studied in panels of extensive (EM) and poor metaboliser (PM) subjects. Drug metabolism was induced in both EM and PM subjects by antipyrine and rifampicin pretreatment as indicated by increased excretion of 6 beta-hydroxycortisol. A 30% increase in metabolic clearance of sparteine was observed in EM subjects following rifampicin administration whereas in PM subjects no effect on the overall elimination of the drug was seen. The data indicate that the regulation of cytochrome P-450 isozyme involved in polymorphic debrisoquine/sparteine metabolism is predominantly under genetic control and that enzyme induction exerts only a marginal effect.

Adult↗
PubMed1986

The genetic polymorphism of sparteine metabolism.

The formation of the two major metabolites of the antiarrhythmic and oxytocic drug sparteine (2- and 5-dehydrosparteine) exhibits a genetic polymorphism. Two phenotypes, extensive (EM) and poor metabolizers (PM) are observed in the population. The frequency of the PM phenotype in various populations (Caucasian and Japanese) ranges from 2.3 to 9%. The metabolism of sparteine is determined by two allelic genes at a single gene locus. PM subjects are homozygous for an autosomal recessive gene. The metabolism of sparteine is predominantly under genetic control as treatment with drugs such as antipyrine and rifampicin known to induce oxidative drug metabolism elicited only marginal changes in sparteine metabolism. The formation of 2-dehydrosparteine in human liver microsomes from EM and PM subjects showed a more than 40-fold difference in Km between EM and PM subjects. However, Vmax-values were almost identical in both groups. These data indicate that the basis of the differences in oxidative capacity between EM and PM subjects is more likely to be due to a variant isozyme with defective catalytic properties than to a decreased amount of the isozyme.

Animals↗