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M Eichelbaum

Publications and source records attributed to M Eichelbaum.

At least 91 records · Page 5Linked to original sources
PubMed1995

Direct gas chromatographic determination of dechloroethylcyclophosphamide following microsomal incubation of cyclophosphamide.

A method for the sensitive determination of dechloroethylcylclophosphamide (3-DCl) in microsomal incubation mixtures was developed. 3-DCl, a side-chain oxidation product of cyclophosphamide (CP), was isolated by extraction with acetic acid ethyl ester following solid-phase extraction on C8 cartridges. Quantification of the metabolite was performed by direct capillary gas chromatography with a nitrogen-phosphorus detector without prior derivatization. The method showed good sensitivity and reproducibility with a detection limit of 1 ng/ml and a limit of quantification of 5 ng/ml. The suitability of the method is shown for the quantification of 3-DCl following incubation of CP with human liver microsomes.

Animals↗
PubMed1995

In vitro characterization of cytochrome P450 catalysed metabolism of the antiemetic tropisetron.

The new 5-hydroxytryptamine type 3 (5HT3) receptor antagonist tropisetron is used in the treatment of chemotherapy-related nausea. The drug is extensively metabolized in man, with the enzymes involved in tropisetron biotransformation being unknown. Identification of these enzymes would make it possible to predict both interindividual variability in plasma concentrations and metabolic interaction potential. The present in vitro study was therefore aimed at identifying and characterizing the cytochrome P450 enzymes catalysing tropisetron metabolism. Enzyme kinetics for formation of 5-hydroxy (5-OH-ICS), 6-hydroxy (6-OH-ICS) and N-demethyl tropisetron (N-De-ICS) were studied in the microsomal fraction of eight human livers (seven livers from extensive metabolizer (EM), one liver from a poor metabolizer (PM) for CYP2D6). Formation of 5-OH-ICS and 6-OH-ICS was biphasic with a high (5-OH: Km 3.9 +/- 2.1 microM; Vmax 1.88 +/- 0.73 pmol/mg/min; 6-OH: Km 4.66 +/- 1.84 microM; Vmax 4.00 +/- 1.77 pmol/mg/min) and low (5-OH: Km 172 +/- 51 microM; Vmax 17.0 +/- 9.4 pmol/mg/min; 6-OH: Km 266.0 +/- 76.0 microM; Vmax 81.4 +/- 27.9 pmol/mg/min) affinity component. The high-affinity component was identified as CYP2D6 which exhibits a genetic polymorphism in man. This component was absent in the PM liver. The low-affinity component was present in EM and PM livers and was identified as CYP3A4. LKM1 antibodies directed against CYP2D6 completely inhibited the high affinity component. Quinidine (0.5 microM) inhibited 5- and 6-hydroxylation at 10-80 microM tropisetron concentrations competitively by 70% with Ki values of 10 and 18 nM, respectively. Stably-expressed CYP2D6 catalysed the formation of both 5-OH-ICS and 6-OH-ICS. Both inhibition experiments and use of stably-expressed enzymes revealed formation of N-De-ICS to be mediated by CYP3A4. Based on in vitro intrinsic clearances CYP2D6-catalysed 5-OH-ICS and 6-OH-ICS is the predominant route of tropisetron elimination. Large phenotype-related differences in total clearance are to be expected after administration of tropisetron. However, in view of the wide therapeutic index of tropisetrone and the rather high Ki for inhibition of the metabolism of other drugs by tropisetron, both the interindividual variability and the interaction potential appear to be of no clinical relevance.

Antiemetics↗
PubMed1995

Highly sensitive and specific gas chromatographic-tandem mass spectrometric method for the determination of trace amounts of antipyrine metabolites in biological material.

A highly sensitive and specific gas chromatographic-tandem mass spectrometric method was developed for the determination of the antipyrine (INN: phenazone) metabolites, norantipyrine, 4-hydroxyantipyrine and 3-hydroxy-methylantipyrine, in biological material. Deuterated analogues of the metabolites were used as internal standards. The method has a limit of quantitation of 5 ng per sample for the determination of norantipyrine, 4-hydroxy-antipyrine and 3-hyddroxymethylantipyrine with coefficients of variation of 19.4, 14.6 and 20.7%, respectively. Precision and accuracy are good over the whole range measured (5-500 ng/sample) with a coefficient of variation, respectively error of determination < or = 20%. Due to its high sensitivity the method can be used to study the formation of these metabolites in microsomal preparations containing only 100 micrograms of protein.

Animals↗
PubMed1995

Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans.

The calcium channel blocker verapamil [2,8-bis-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile+ ++] undergoes extensive biotransformation in man. We have previously demonstrated cytochrome P450 (CYP) 3A4 and 1A2 to be the enzymes responsible for verapamil N-dealkylation (formation of D-617 [2-(3,4-dimethoxyphenyl)-5-methylamino-2-isopropylvaleronitrile], and verapamil N-demethylation (formation of norverapamil [2,8-bis-(3,4-dimethoxyphenyl)-2-isopropyl-6-azaoctanitrile]), while there was no involvement of CYP3A4 and CYP1A2 in the third initial metabolic step of verapamil, which is verapamil O-demethylation. This pathway yields formation of D-703 [2-(4-hydroxy-3-methoxyphenyl)-8-(3,4-dimethoxyphenyl)-6-methyl-2-isopro pyl-6-azaoctanitrile] and D-702 [2-(3,4-dimethoxyphenyl)-8-(4-hydroxy-3-methoxyphenyl)-6-methyl-2-isopro pyl-6-azaoctanitrile]. The enzymes catalyzing verapamil O-demethylation have not been characterized so far. We have therefore identified and characterized the enzymes involved in verapamil O-demethylation in humans by using the following in vitro approaches: (I) characterization of O-demethylation kinetics in the presence of the microsomal fraction of human liver, (II) inhibition of verapamil O-demethylation by specific antibodies and selective inhibitors and (III) investigation of metabolite formation in microsomes obtained from yeast strain Saccharomyces cerevisiae W(R), that was genetically engineered for stable expression of human CYP2C8, 2C9 and 2C18. In human liver microsomes (n=4), the intrinsic clearance (CLint), as derived from the ratio of Vmax/Km, was significantly higher for O-demethylation to D-703 compared to formation of D-702 following incubation with racemic verapamil (13.9 +/- 1.0 vs 2.4 +/- 0.6 ml*min-1*g-1, mean+/-SD; p<0.05), S-verapamil (16.8 +/- 3.3 vs 2.2 +/- 1.2 ml* min-1*g-1, p<0.05) and R-verapamil (12.1 +/- 2.9 vs 3.6 +/- 1.3 ml*min-1*g-1; p<0.05), thus indicating regioselectivity of verapamil O-demethylation process. The CLint of D-703 formation in human liver microsomes showed a modest but significant degree of stereoselectivity (p<0.05) with a S/R-ratio of 1.41 +/- 0.17. Anti-LKM2 (anti-liver/kidney microsome) autoantibodies (which inhibit CYP2C9 and 2C19) and sulfaphenazole (a specific CYP2C9 inhibitor) reduced the maximum rate of formation of D-703 by 81.5 +/- 4.5% and 45%, that of D-702 by 52.7 +/- 7.5% and 72.5%, respectively. Both D-703 and D-702 were formed by stably expressed CYP2C9 and CYP2C18, whereas incubation with CYP2C8 selectively yielded D-703. In conclusion, our results show that enzymes of the CYP2C subfamily are mainly involved in verapamil O-demethylation. Verapamil therefore has the potential to interact with other drugs which inhibit or induce these enzymes.

Calcium Channel Blockers↗
PubMed1995

Stereoselectivity in cardiovascular and biochemical action of calcium antagonists: studies with the enantiomers of the dihydropyridine nitrendipine.

OBJECTIVES: The cardiovascular and biochemical effects of R- and S-nitrendipine were studied in six healthy subjects in a single-blind placebo-controlled study. METHODS: After received oral doses of placebo, 20 mg R-, 80 mg R- (n = 5), 20 mg S-, and 20 mg racemic nitrendipine, heart rate, systolic, diastolic, and mean arterial blood pressure, leg blood flow, peripheral vascular resistance, plasma renin activity, norepinephrine, epinephrine, dopamine, and aldosterone plasma levels were measured before and up to 3 hours after administration. RESULTS: Neither placebo nor 20 or 80 mg R-nitrendipine caused significant changes of cardiovascular and biochemical parameters. After 20 mg S-nitrendipine and 20 mg racemic nitrendipine, significant changes in diastolic blood pressure (-9.1/-7.4 mm Hg), heart rate (+21.9/+17.3 beats/min), leg blood flow (+6.8 ml.min-1.gm tissue-1), peripheral vascular resistance (-16.9 mm Hg.min.gm tissue.ml-1), norepinephrine (+476/+281 ng.L-1), and plasma renin activity (+9.5/+3.6 ng.ml-1.hr-1) were observed. The changes in cardiovascular and biochemical parameters were closely related to the serum S-nitrendipine concentrations. CONCLUSIONS: It can be concluded that, after administration of the racemate, the S-enantiomer is responsible for the cardiovascular and biochemical effects observed and that S-nitrendipine is at least an order of magnitude more potent than the R-enantiomer.

Administration, Oral↗
PubMed1995

"It's the genes, stupid". Molecular bases and clinical consequences of genetic cytochrome P450 2D6 polymorphism.

In this review we highlight the information available on the genetic polymorphism of cytochrome P4502D6 expression in man. An absent function of this enzyme is observed in 7-10 percent of the Caucasian population which are referred to as Poor metabolizers as opposed to the remainder of the population (Extensive Metabolizers). More than 30 widely used drugs have been identified as substrates for CYP2D6. Disposition and action of these compounds depend on the individual phenotype. Both the molecular bases of the variable enzyme activity and the consequences for drug therapy are outlined. While mutations on the DNA level have been investigated in great detail larger scale clinical trials are lacking and information on therapeutic consequences of CYP2D6 mediated polymorphic drug oxidation is restricted to case reports. Besides these implications for drug metabolism several lines of evidence indicate that CYP2D6 could be involved in biotransformation of endogenous compounds.

Animals↗
PubMed1995

The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions.

1. Little information is available about the pharmacokinetic interactions of anticancer drugs in man. However, clinically significant drug interactions do occur in cancer chemotherapy, and it is likely that important interactions have not been recognized. 2. Specific cytochrome P450 (CYP) enzymes have been recently shown to be involved in the metabolism of several essential anticancer agents. In particular, enzymes of the CYP3A subfamily play a role in the metabolism of many anticancer drugs, including epipodophyllotoxins, ifosphamide, tamoxifen, taxol and vinca alkaloids. CYP3A4 has been shown to catalyse the activation of the prodrug ifosphamide, raising the possibility that ifosphamide could be activated in tumour tissues containing this enzyme. 3. As examples of recently found, clinically significant interactions, cyclosporin considerably increases plasma doxorubicin and etoposide concentrations. Although cyclosporin and calcium channel blockers may influence the pharmacokinetics of certain anticancer agents by inhibiting their CYP3A mediated metabolism, it is more likely that these P-glycoprotein inhibitors inhibit P-glycoprotein mediated drug elimination. 4. Appropriate caution should be exercised when combining P-glycoprotein inhibitors and potential CYP3A inhibitors with cancer chemotherapy.

Antineoplastic Agents↗
PubMed1995

Mechanism of cytochrome P450 2D6-catalyzed sparteine metabolism in humans.

Two different reaction mechanisms for the formation of the two human enamine-structured sparteine metabolites by cytochrome P450 2D6 have been discussed in the literature. These mechanisms are either initial one-electron oxidation of N1 of sparteine followed by deprotonation of the aminium radical cation, resulting in the formation of different carbon radicals and oxygen rebound of the carbon radicals, or oxidation of the carbon atoms adjacent to N1 by the enzyme, directly producing the respective carbon radicals. With a spectrum of deuterium-labeled isotopomers of sparteine, stereoselectivity and kinetic isotope effects of human sparteine metabolism were investigated by in vitro and in vivo experiments and were compared with chemical oxidation of 17-oxosparteine. These experiments revealed that the major human sparteine metabolite 2,3-didehydrosparteine is formed via highly stereoselective abstraction of the 2 beta-hydrogen atom; the deuterium label was completely retained during metabolism when 2R-[2H]sparteine was used as substrate. Chemical oxidation of 17-oxosparteine by Ce4+, as a model for one-electron oxidation of N1 of a sparteine-like structure, resulted in the sole formation of the 5,6-unsaturated enamine, and no 2,3-unsaturated enamine, structurally equivalent to the human major metabolite, was found. An unequivocal discrimination between the two possible reaction mechanisms was not possible by simple interpretation of the magnitude of the kinetic deuterium isotope effects. However, results of competitive and noncompetitive experiments revealed the presence of a nondissociative enzymatic mechanism for the formation of the two sparteine metabolites, i.e., the sparteine molecule that is bound to the substrate binding site of cytochrome P450 2D6 performs orientational changes without dissociating from the activated enzyme/substrate complex before the product-determining first irreversible reaction step. These results agree with the hypothesis that sparteine metabolism proceeds by direct carbon oxidation. Because electron transfer from amines to P450 may occur over some distance, the possibility of a sequential electron-proton transfer reaction during sparteine metabolism cannot be ruled out completely as an alternative reaction mechanism for sparteine metabolism.

Binding, Competitive↗
PubMed1994

A missense mutation in exon 6 of the CYP2D6 gene leading to a histidine 324 to proline exchange is associated with the poor metabolizer phenotype of sparteine.

The sparteine/debrisoquine polymorphism is a clinically important genetic deficiency of cytochrome P4502D6-catalyzed oxidative drug metabolism. 5-10% of Caucasians designated as poor metabolizers have a severely impaired capacity to metabolize more than 30 therapeutically used drugs. Genotyping of a random Caucasian population for the known cytochrome P4502D6 mutations A, B and D which are associated with the poor metabolizer phenotype has revealed a substantial number of misclassified poor metabolizers indicating the existence of one or more unknown mutations which cannot be identified with the currently available genotyping assays. Therefore we have cloned and sequenced one nonfunctional cytochrome P4502D6 allele of a misclassified poor metabolizer and could identify a single missense mutation designated E mutation at position 3023(A-C) in exon 6. Direct sequencing analysis, FokI restriction analysis and a newly developed allele-specific polymerase chain reaction assay were applied to analyze for this mutation in a population study. Three out of 97 randomly selected Caucasians were carriers of this mutation and thus the E allele has a frequency of 1.5% (confidence interval95% = 0.33 - 4.54%). Since only 2 out of 4 misclassified poor metabolizers carried the E mutation, additional unknown mutant alleles must exist. Computer modelling suggests that the E mutation, which results in a histidine to proline exchange in position 324 of the protein, may cause an alteration of the 3D structure of CYP2D6 in close vicinity to the active site thereby leading to total loss of enzyme function.

Alleles↗
PubMed1994

Rapid determination of CYP2D6 phenotype during propafenone therapy by analysing urinary excretion of propafenone glucuronides.

Metabolism of the antiarrhythmic, propafenone, cosegregates with the sparteine/debrisoquine polymorphism. Patients devoid of CYP2D6 activity have a higher incidence of adverse effects than those with normal enzyme function. In this paper we present a method for rapid assignment of CYP2D6 phenotype using urinary excretion of intact glucuronides of propafenone (PPFG). After establishing an HPLC assay, urinary excretion of PPFG was quantified during one dosage interval and related to individual CYP2D6 activity as determined by phenotyping. We observed a close correlation of urinary excretion of PPFG with individual CYP2D6 activity (r = 0.84, P < 0.01) and conclude that this method is suitable for rapid assignment of phenotype during propafenone therapy.

Aged↗
PubMed1994

Variable disposition kinetics and electrocardiographic effects of flecainide during repeated dosing in humans: contribution of genetic factors, dose-dependent clearance, and interaction with amiodarone.

We studied the influence of cytochrome P450 2D6 (CYP2D6) on the steady-state disposition kinetics and the electrocardiographic effects of flecainide at two doses and during combination with amiodarone. Seven extensive and five poor metabolizers of dextromethorphan were studied during a three-period crossover study. All subjects received 50 mg flecainide every 12 hours, alone or together with 200 mg amiodarone every 12 hours, and 100 mg flecainide every 12 hours for 5 days. Mean steady-state plasma concentration of flecainide and QRS change from predrug value did not differ significantly among extensive and poor metabolizer subjects during each study period. Except for a shortened elimination half-life and nonlinear kinetics in extensive metabolizer subjects, phenotype had no significant influence on flecainide pharmacokinetics. Combination with amiodarone resulted in an increase in mean flecainide plasma concentration and effect in subjects with both phenotypes. Our findings indicate that CYP2D6 phenotype predicts flecainide nonlinear kinetics and flecainide half-life but has no influence on electrocardiographic effects during repeated administration of flecainide or on the extent of the amiodarone-flecainide interaction.

Administration, Oral↗
PubMed1994

Unpredictability of flecainide plasma concentrations in patients with renal failure: relationship to side effects and sudden death?

We report a retrospective evaluation of plasma concentrations of flecainide obtained from five dialysis patients during chronic oral treatment. A more than sevenfold variation in the dose/concentration relationship was observed. Plasma concentrations of flecainide above 1,200 ng/ml appeared to be associated with serious side effects and in one case with sudden death. Therefore, flecainide should be used with extreme caution in patients with impaired renal function. Frequent therapeutic drug monitoring should be mandatory.

Aged↗
PubMed1994

The influence of environmental and genetic factors on CYP2D6, CYP1A2 and UDP-glucuronosyltransferases in man using sparteine, caffeine, and paracetamol as probes.

The impact of gender, use of oral contraceptive steroids (OCS), coffee consumption and of smoking on the metabolism of sparteine, caffeine, and paracetamol was studied in 194 randomly selected subjects (98 male and 95 female). Thirty-eight of the male volunteers were cigarette smokers, 40 of the female subjects were smokers and/or users of OCS. The metabolic ratio of sparteine oxidation (MRs) showed a trimodal distribution. 7.7% of the subjects had a MRs > 20 and thus were poor metabolizers (PMs). Within the extensive metabolizer (EM) subjects, a distinct subgroup accounting for 11% was observed with 20 > MRs > 1.2. Six of the 15 phenotypical PMs were heterozygous EMs by genotyping. This indicates the existence of one or several CYP2D6 mutations which cannot be identified by the currently employed genotyping methods. In each subgroup, i.e. smokers/OCS and non-smokers/non-OCS, the cumulative frequency distribution of the heterozygous (wt/B) phenotype caused a shift to higher MRs compared with the wild-type homozygotes (wt/wt). Thus, for the in vivo activity of CYP2D6, genetic determinants prevail over environmental factors. Smoking, use of oral contraceptive steroids, caffeine consumption, or gender had no influence on sparteine metabolism. The distribution of the paracetamol glucuronide/paracetamol metabolic ratio appeared to be unimodal although skewed. Glucuronidation capacity was clearly affected by gender, OCS use and smoking. It was higher in male than in female subjects. Male smokers had the highest, and female non-smokers/non-OCS users the lowest metabolic ratio. CYP1A2 activity, as determined by a caffeine metabolic ratio ((AFMU + 1X + 1U)/1, 7U), was multimodally distributed and was clearly increased in smokers. It was significantly correlated to paracetamol glucoronidation in male heavy smokers (r=0.85), suggesting an element of co-regulation of CYP1A2 and of paracetamol conjugating UDP-glucuronosyltransferase isozymes, including UGTI.6.

Acetaminophen↗
PubMed1994

An enantiomer-enantiomer interaction of (S)- and (R)-propafenone modifies the effect of racemic drug therapy.

BACKGROUND: Therapy with racemic compounds produces effects that can be attributed to both (S)- and (R)-enantiomers. Here we have tested the hypothesis that an enantiomer-enantiomer interaction would modulate the effects of treatment with a racemate, the antiarrhythmic propafenone. Previous studies have shown that while the enantiomers of propafenone exert similar sodium channel-blocking (QRS widening) effects, it is the (S)-enantiomer that produces beta-blockade; moreover, we have demonstrated recently that (R)-propafenone inhibits the metabolism of (S)-propafenone in vitro. METHODS AND RESULTS: This single-blind, randomized study compared the effects of (R/S)-, (S)-, (R)-propafenone (150 mg q 6 hours for 4 days) and placebo on QRS duration (delta QRS) and on maximum exercise heart rate (delta HRmax), an index of beta-blockade. The clearance of (S)-propafenone was significantly lower (-55 +/- 24%, P < .001) during treatment with (R/S)-propafenone than with the (S)-enantiomer alone, and delta HRmax was significantly altered during (R/S)-propafenone (-8.8 +/- 6.6 beats per minute; P < .01) and during (S)-propafenone (-4.3 +/- 4.8 beats per minute; P < .01) but not during (R)-propafenone (-1.8 +/- 6.4 beats per minute) or placebo (0.3 +/- 7.1 beats per minute). In contrast, (R/S)-, (S)-, and (R)-propafenone all prolonged QRS compared with placebo. CONCLUSIONS: These data indicate that (R)-propafenone impairs the disposition of (S)-propafenone in humans. As a result, the beta-blocking effects of 150 mg of racemic propafenone (75 mg of the [S]-enantiomer) were more pronounced than those of 150 mg of (S)-propafenone alone. Thus, the effects of racemic drug therapy are not necessarily those predicted by summation of the effects of the individual enantiomers.

Adrenergic beta-Antagonists↗
PubMed1994

Endogenous codeine and morphine in poor and extensive metabolisers of the CYP2D6 (debrisoquine/sparteine) polymorphism.

Codeine and morphine are endogenous substances. Following administration of exogenous codeine the biotransformation to morphine is catalyzed by CYP2D6, which exhibits a genetic so-called debrisoquine/sparteine polymorphism which is expressed in two phenotypes, the extensive and poor metaboliser phenotypes. Poor metabolisers form only trace amounts of morphine. If endogenous morphine is biosynthesised in humans via similar routes as in the poppy plant, two of the steps involved are mediated by CYP2D6, namely thebaine O-demethylation to oripavine and codeine O-demethylation to morphine. Poor metabolisers should therefore have a much lower endogenous morphine formation than extensive metabolisers. The urinary excretion of endogenous codeine and morphine were investigated in 20 extensive and 20 poor metabolisers of CYP2D6. Substantial interindividual variation in codeine (7-6851 pmol/24 hr) and morphine (32-35471 pmol/24 hr) excretion was observed. However, there were no phenotype-related differences in endogenous codeine and morphine excretion. Administration of the competitive CYP2D6 inhibitor quinidine had no significant effect on endogenous codeine and morphine excretion in extensive metabolisers. In conclusion, in contrast to exogenous codeine O-demethylation to morphine CYP2D6 appears not to be involved in the biosynthesis of morphine in humans.

Adult↗
PubMed1993

Enantioselective gallopamil protein binding.

The protein binding of the enantiomers of gallopamil has been investigated in solutions of human serum albumin, alpha 1-acid glycoprotein and serum. Over the range of concentrations attained after oral gallopamil administration, the binding of both enantiomers to albumin, alpha 1-acid glycoprotein, and serum proteins was independent of gallopamil concentration. The binding to both human serum albumin (40 g/liter) [range of fraction bound (fb) R: 0.624 to 0.699; S: 0.502 to 0.605] and alpha 1-acid glycoprotein (0.5 g/liter) (range of fb R: 0.530 to 0.718; S: 0.502 to 0.620) was stereoselective, favoring the (R)-enantiomer (predialysis gallopamil concentrations 2.5 to 10,000 ng/ml). When the enantiomers (predialysis gallopamil concentration 10 ng/ml) were studied separately in drug-free serum samples from six healthy volunteers the fraction of (S)-gallopamil bound (fb: 0.943 +/- 0.016) was lower (P < 0.05) than that of (R)-gallopamil (fb: 0.960 +/- 0.010). The serum protein binding of both (R)- and (S)-gallopamil was unaffected by their optical antipodes (fb R: 0.963 +/- 0.011; S: 0.948 +/- 0.015) indicating that at therapeutic concentrations a protein binding enantiomer-enantiomer interaction does not occur. The protein binding of (R)- and (S)-gallopamil ex vivo 2 h after single dose oral administration of 50 mg pseudoracemic gallopamil (fb R: 0.960 +/- 0.010: predialysis [R] 6.9 to 35.3 ng/ml; S: 0.943 +/- 0.016: predialysis [S] 9.5 to 30.7 ng/ml) was comparable to that observed in vitro in drug-free serum. Gallopamil metabolites formed during first-pass following oral administration, therefore, do not influence the protein binding of (R)- or (S)-gallopamil.

Administration, Oral↗