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Biomedical subjects

M Eichelbaum

Publications and source records attributed to M Eichelbaum.

At least 181 records · Page 10Linked to original sources
PubMed1986

Carbamazepine-danazol drug interaction: its mechanism examined by a stable isotope technique.

Carbamazepine (CBZ) labeled with 15N was used to investigate the mechanism of its pharmacokinetic interaction with the antiestrogenic steroid danazol during treatment of a patient with epilepsy. Danazol led to a pronounced inhibition of CBZ metabolism. During danazol coadministration, CBZ elimination half-life increased from a pretreatment value of 11 to 24.3 h. Carbamazepine plasma clearance decreased from 57.7 to 23.2 ml/h/kg. Kinetic analysis of the plasma concentration-time curves and urinary excretion of [15N]trans-CBZ-diol revealed that danazol inhibited the epoxide-trans-diol pathway of carbamazepine metabolism. Observations in five other female patients confirm that the steady-state plasma concentrations of UCBZ increase between 50 and 100% during coadministration of danazol.

Adult↗
PubMed1985

Pharmacokinetics of oral and intravenous rifampicin during chronic administration.

We investigated the pharmacokinetics of rifampicin and its major metabolites, 25-desacetylrifampicin and 3-formylrifampicin, in two groups of six patients with active pulmonary tuberculosis, who received either multiple oral or intravenous rifampicin therapy in combination with intravenous isoniazid and ethambutol. Serum concentrations of rifampicin were each determined after a single oral and intravenous test dose of 600 mg rifampicin at the beginning and after 1 and 3 weeks of tuberculostatic treatment. Analysis of rifampicin and its metabolites was performed by high-pressure liquid chromatography. It was found that, due to autoinduction of its metabolizing hepatic enzymes, the systemic clearance of rifampicin increased from 5.69 to 9.03 l/h after 3 weeks of multiple dosing. The volume of distribution of the drug was constant over the period of this study. The bioavailability of the active, orally administered rifampicin decreased from 93% after the first single oral dose to 68% after 3 weeks of oral and intravenous rifampicin therapy. Relating to the increase in systemic (hepatic) clearance, a bioavailability no lower than 90% can be predicted. The reduction to 68% indicates that, in addition to an increase of hepatic metabolism, an induction of a prehepatic "first-pass" effect resulted from multiple rifampicin doses. Our study of rifampicin metabolites confirm that prehepatic metabolism was induced, since a higher metabolic ratio resulted after the oral doses than after the intravenous rifampicin test doses. A preabsorptive process can therefore be excluded as a cause of reduced bioavailability.

Administration, Oral↗
PubMed1985

Pharmacokinetics of N-propylajmaline in relation to polymorphic sparteine oxidation.

In order to determine whether the metabolism of the antiarrhythmic drug N-propylajmaline is under the same genetic control as sparteine metabolism, the pharmacokinetics of this antiarrhythmic drug were studied in a groups of six extensive and four poor metabolizers of sparteine. Pronounced differences in terminal half-life, total plasma clearance, metabolic clearance and urinary excretion of N-propylajmaline were observed between extensive and poor metabolizers. A close relationship between the total clearance and metabolic clearance of N-propylajmaline and sparteine could be demonstrated. Clinically available N-propylajmaline is a 55% to 45% mixture of the i- and n-diastereomers. The extensive metabolizers exhibited stereoselective metabolism; the i-diastereomer was preferentially metabolized. Poor metabolizers were characterized by a loss of this stereoselective metabolism. Five subjects were treated for 7 days with a daily N-propylajmaline dosage of either 60 mg or 20 mg. Since a close relationship between the clearance of N-propylajmaline and the metabolic ratio of sparteine had been observed after single dosing the metabolic ratio of sparteine was used to predict N-propylajmaline steady-state plasma concentrations during multiple dosing. Only in two extensive metabolizers with a metabolic ratio less than 0.4 predicted and observed, steady-state plasma concentrations were in good agreement. In the other three subjects observed steady-state plasma concentrations were appreciably higher than predicted. In these three subjects metabolic N-propylajmaline clearance decreased indicating saturation N-propylajmaline metabolism during multiple dosing. The data indicate that N-propylajmaline metabolism is subject to a genetic polymorphism controlled by the sparteine/debrisoquine gene locus.

Adult↗
PubMed1985

Determination of isoniazid, acetylisoniazid, acetylhydrazine and diacetylhydrazine in biological fluids by high-performance liquid chromatography.

A high-performance liquid chromatographic assay for the determination of isoniazid, acetylisoniazid, acetylhydrazine and diacetylhydrazine (plasma and urine) was developed. The m-chlorobenzoyl derivatives of isoniazid, acetylhydrazine and the internal standard propionylhydrazine were prepared, separated on a RP-18 column and detected at 220 nm. Acetylisoniazid, diacetylhydrazine and the internal standard dipropionylhydrazine were converted to isoniazid, acetylhydrazine, and propionylhydrazine by acidic hydrolysis and subsequently derivatized with m-fluorobenzoyl chloride, separated on a RP-18 column and detected at 220 nm. The lower limits of detection in plasma are acetylhydrazine 0.5 nmol/ml, isoniazid 1.0 nmol/ml, diacetylhydrazine 1.0 nmol/ml and acetylisoniazid 2.0 nmol/ml, and in urine, acetylhydrazine 10 nmol/ml, isoniazid 15 nmol/ml, diacetylhydrazine 20 nmol/ml and acetylisoniazid 40 nmol/ml. This method is sensitive, reproducible, accurate and precise; therefore, it is well suited for detailed pharmacokinetic studies.

Body Fluids↗
PubMed1985

Diltiazem, verapamil, and quinidine in patients with chronic atrial fibrillation.

The comparative effects of diltiazem and verapamil in 30 patients with long-standing atrial fibrillation were evaluated in a prospective clinical trial. After a one- to two-day washout period during which drugs other than digoxin were withdrawn, patients were randomly assigned to diltiazem or verapamil treatment groups. All therapy was double blind. Both drugs were given in ascending doses as follows: days 1-6 (part I): diltiazem, 180 mg/d, or verapamil, 240 mg/d; days 7-12 (part II): diltiazem, 360 mg/d, or verapamil, 480 mg/d. Patients failing to convert to sinus rhythm after 12 days had dosage reduced to 180 mg/d of diltiazem or 240 mg/d of verapamil, and quinidine, 750 mg/d, was coadministered for another six days (part III). Medication compliance was verified by frequent measurement of serum drug concentrations. Three verapamil patients dropped out during part I due to adverse reactions (dyspnea, pulmonary congestion, skin rash, or hepatotoxicity). The higher dosage of either verapamil or diltiazem in part II was not well tolerated, and in eight patients part III had to be initiated early due to symptomatic bradycardia. Only one patient in the diltiazem group converted to sinus rhythm, whereas five converted with verapamil (two with verapamil alone, three when combined with quinidine). Thus, diltiazem and verapamil alone are unlikely to convert atrial fibrillation to sinus rhythm. The combination of verapamil and quinidine, however, is a potentially useful pharmacologic approach, having converted atrial fibrillation to sinus rhythm in nearly 50% of patients.

Anti-Arrhythmia Agents↗
PubMed1985

Inter-ethnic difference in sparteine oxidation among Ghanaians and Germans.

Sparteine oxidation, which exhibits genetic polymorphism in various Caucasian populations, was studied in 154 unrelated Ghanaian subjects. Mean total urinary recovery of sparteine and 2- and 5-dehydrosparteines (56.6 +/- 16.6% of the dose) was not different from Caucasians. In contrast to Caucasians, amongst whom 6.3 to 9% of the population are poor metabolizers (PM), no PM subject was observed in the Ghanaian population sample. The data appear to indicate allelic differences between Caucasians and Ghanaians in the gene encoding the synthesis of the P-450 isozyme involved in polymorphic sparteine oxidation.

Black People↗
PubMed1985

The effect of dextro-, levo-, and racemic verapamil on atrioventricular conduction in humans.

To study the dromotropic effects of dextro(D)- and levo(L)-verapamil on atrioventricular (AV) conduction in humans, we investigated the prolongation of the PR interval following intravenous administrations of each isomer and racemic preparation (D, 5, 25, and 50 mg; L, 5, 7.5, and 10 mg; racemic, 10 mg). The plasma drug concentration-effect relationship was analyzed by log-linear regression and the sigmoidal Emax model. The sigmoidal Emax model provided a significantly better fit for the data than log-linear regression (p less than 0.01). Maximum drug effect (Emax) and plasma drug concentration associated with 50% Emax (EC50) were calculated by means of the Emax model. The dromotropic potency of each isomer was assessed in terms of EC50 and the drug concentration associated with a 10% PR prolongation from the basal level calculated by the Emax model. The results demonstrated that L-verapamil was 10 and 18 times more potent than D-verapamil in terms of EC50 (D, 188.9 +/- 108.4 ng/ml; L, 17.7 +/- 11.3 ng/ml; p less than 0.05) and drug concentration associated with 10% PR prolongation (D, 166.6 +/- 48.1 ng/ml; L, 9.1 +/- 2.8 ng/ml; p less than 0.01), respectively. A stereospecific difference in plasma protein binding was observed (D, 93.7 +/- 2.2%; L, 88.5 +/- 1.6%; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Effects of d,l-verapamil on atrioventricular conduction in relation to its stereoselective first-pass metabolism.

After the oral administration of 160 mg pseudoracemic verapamil (80 mg dideuterodextro (d) isomer and 80 mg levo (l) isomer), the prolongation of the PR interval was assessed in relation to d- and l-verapamil plasma concentrations. Concentration-effect curves were analyzed with the sigmoidal Emax model. Because of stereoselective first-pass metabolism, the mean plasma d- to l-verapamil concentration ratio of 4.5 +/- 1.2 was substantially greater than that of 2.1 +/- 0.3 after intravenous dosing. Compared with the concentration after intravenous injection, the total verapamil concentration after oral dosing consisted of a substantially smaller proportion of the more potent l-isomer. These differences in isomer composition of the total verapamil plasma concentration as a result of the route of administration explain the diminished negative dromotropic potency of racemic verapamil after oral dosing. The concentration required to reach 50% of the maximum effect (EC50) for total verapamil concentration was 129.0 +/- 22.9 ng/ml, which was more than three times higher than that after intravenous injection. To assess the relative contributions of the d- and l-isomers to overall dromotropic potency, changes in the PR interval were measured after separate oral dosing with 250 mg d-verapamil and 100 mg l-verapamil. The EC50 showed an 11-fold difference between the l- (36.9 +/- 14.7 ng/ml) and d- (363.1 +/- 64.2 ng/ml) isomers. The EC50 for the l-isomer concentration after oral pseudoracemic verapamil (20.2 +/- 6.3 ng/ml) did not differ significantly from that after l-verapamil alone (36.9 +/- 14.7 ng/ml). We conclude that the l-isomer determines the negative dromotropic effects of verapamil and that the d-isomer is of minor importance.

Administration, Oral↗
PubMed1985

Dissociation of co-regulatory control of debrisoquin/phenformin and sparteine oxidation in Ghanaians.

The ability to oxidize sparteine to form 2- and 5-dehydrosparteine was studied in 154 healthy Ghanaians. Although the urinary metabolic sparteine/dehydrosparteines ratio varied widely (from 0.14 to 12.5), in contrast to observations in several Caucasian population groups the ratios were not bimodally distributed and no phenotypically poor oxidizers of sparteine were found. The ability of these same subjects to oxidize debrisoquin and phenformin was also studied in 141 and 143 subjects. Of the 141 subjects dosed with debrisoquin, 10 proved to be poor oxidizers, and of the 143 subjects dosed with phenformin, 11 were poor oxidizers. All the poor oxidizers of debrisoquin were also poor oxidizers of phenformin. The 10 confirmed poor metabolizers of debrisoquin, who had debrisoquin metabolic ratios ranging from 14.4 to 52.0, had sparteine metabolic ratios ranging only from 0.15 to 12.5. Whereas Caucasian poor metabolizers of sparteine excrete less than 2.0% of a dose as dehydrosparteines, the mean excretion of dehydrosparteines in our 10 subjects was 20.6% +/- 13.2%. The overall rank correlation between the sparteine and debrisoquin metabolic ratios was low (rs = 0.47), while the coefficient of determination for linear regression (r2) was only 0.17. Our data show that the ability of Ghanaians to oxidize sparteine is largely independent of their capacity for debrisoquin oxidation and is indicative of a major interethnic difference in the genetic control of these reactions.

Administration, Oral↗
PubMed1984

Characterization of a common genetic defect of cytochrome P-450 function (debrisoquine-sparteine type polymorphism)--increased Michaelis is Constant (Km) and loss of stereoselectivity of bufuralol 1'-hydroxylation in poor metabolizers.

In order to define the mechanism of the debrisoquine-sparteine type genetic polymorphism of drug oxidation we studied the kinetics of bufuralol 1'-hydroxylation in liver microsomes from extensive and poor metabolizers and in a purified reconstituted human cytochrome P-450 isozyme with high activity for bufuralol 1'-hydroxylation, P-450[buf]. In extensive metabolizer microsomes the enzymatic reaction displayed apparent Michaelis-Menten kinetics and the (+)-isomer was preferentially metabolized. By contrast, the enzymatic reaction in poor metabolizer microsomes was characterized by a 4- to 5-fold increase in Km and by a loss of stereoselectivity. In a non-membraneous reconstituted system containing NADPH cytochrome P-450 reductase, a NADPH regenerating system and phospholipids, P-450[buf] exhibited an almost complete substrate stereoselectivity for (+)-isomer 1'-hydroxylation. It is concluded that the purified cytochrome P-450[buf] is the target of the debrisoquine-sparteine type oxidation polymorphism and that poor metabolizers have a quantitative or qualitative deficiency of this isozyme.

Cytochrome P-450 Enzyme System↗
PubMed1984

Polymorphic drug oxidation in humans.

Genetic polymorphisms in the oxidative metabolism of debrisoquine, mephenytoin, phenformin, sparteine, and tolbutamide have been discovered during recent years. Among these pharmacogenetic conditions, polymorphic oxidation of debrisoquine and sparteine has been intensively studied. Two phenotypes, the extensive (EM) and the poor (PM) metabolizers, have been observed in all populations so far investigated. The PM phenotype exhibits a grossly impaired or nearly absent capacity to metabolize these drugs. The incidence of the PM phenotype in European populations ranges from 5 to 9%. Pronounced variations in the incidence of the PM phenotype have been demonstrated among different ethnic groups. The metabolism of debrisoquine and sparteine is determined by two alleles at a single gene locus; PMs are homozygous for an autosomal recessive gene. Because of markedly impaired metabolism, the PM phenotype develops side effects if normal doses of debrisoquine and sparteine are administered. Defective metabolism in the PM phenotype is not restricted to debrisoquine and sparteine. Impaired metabolism of guanoxan , phenformin, perhexiline, methoxyamphetamine, phenacetin, encainide, metoprolol, alprenolol, bufuralol, nortriptyline, and desipramine have been described. As a consequence of impaired metabolism of these drugs, toxicity and therapeutic failure are observed in the PMs. With regard to molecular mechanisms, studies with microsomes from human liver provide evidence that in the PM phenotype a cytochrome P-450 isozyme is either missing or functionally inadequate.

Cytochrome P-450 Enzyme System↗
PubMed1984

Serum gentamicin concentrations during intratracheal administration.

In artificially ventilated patients, intratracheal aminoglycoside administration is used as a form of prophylaxis of broncho-pulmonary infections. In artificially ventilated patients with multiple organ failure, serum gentamicin concentrations were measured dependent on renal function after endotracheal administration. A standard commercial ampule of 40 mg gentamicin in a 1 ml solution was injected in undiluted form, intratracheally through the tubus , every 6 h. In the patients without renal failure, values over 1 microgram/ml were only found in certain individual cases and reached a maximum of 1.5 micrograms/ml. In patients with renal failure even after prolonged application, the average serum concentrations were between 2 and 3.5 micrograms/ml. In a very few cases, however, levels of up to 10.5 micrograms/ml were measured. The daily serum pattern revealed a distinct dependence on the administration; 1 h after administration there was an increase in the serum concentrations which decreased to the initial levels after 6 h. When patients with renal impairment are given an aminoglycoside intratracheally, serum levels of up to 10.5 micrograms/ml may be reached and thus additional systemic aminoglycoside therapy should be avoided.

Acute Kidney Injury↗
PubMed1984

Drug toxicity and hormonal dysfunction.

Abnormal levels of hormones can exert profound changes in drug disposition and the number and affinity of receptors. In endocrine diseases a variety of organ functions change. These disease related changes in the function of organs involved with the distribution, metabolism and excretion of drugs can profoundly alter drug disposition. If not taken into account when devising dosage regimens drug toxicity can result.

Adrenal Gland Neoplasms↗
PubMed1984

Inter- and intra-subject variation in the first-pass elimination of highly cleared drugs during chronic dosing. Studies with deuterated verapamil.

The pharmacokinetics of verapamil in five healthy volunteers were investigated on 4 occasions during chronic administration of deuterated verapamil. There was no statistically significant difference in oral clearance, terminal half-life, bioavailability, morning trough level and peak concentration or in the time of their occurrence on the four occasions. The plasma clearance, however, exhibited considerable inter- and intra-individual variation, ranging between 26.3% and 85.4% and 12.0% and 48.0%, respectively. Comparison of these pharmacokinetic parameters with data from previous single dose studies in the same subjects revealed a significant (p less than 0.05) decrease in the clearance and an increase in the apparent bioavailability of verapamil during chronic administration, although no difference in the half-life was found. Due to the considerable variation in the oral clearance of verapamil during chronic dosing, steady-state conditions in a strict pharmacokinetic sense may never be attained, and pharmacokinetic data obtained in single dose studies will be of limited value in predicting steady-state plasma concentrations.

Administration, Oral↗
PubMed1984

Theophylline metabolism in relation to antipyrine, debrisoquine, and sparteine metabolism.

Theophylline plasma clearance (Clp) and clearance to its metabolites ( Clm ), as well as antipyrine saliva clearance ( Clsal ) and its Clm were compared in a crossover study in 25 healthy subjects. They were selected with regard to smoking status (nine smokers, 16 nonsmokers) and oxidation phenotype of debrisoquine and sparteine (six poor metabolizers [PMs] and 19 extensive metabolizers [EMs]). Clm of theophylline (1,3-dimethyluric acid, 1-methyluric acid, and 3-methylxanthine) correlated (r greater than or equal to 0.92) to each other and to total theophylline Clp (r greater than or equal to 0.97). Smokers had higher Clm to all metabolites, particularly by the N-demethylation pathways. After correction for the effect of smoking, there was no difference between EMs and PMs with regard to theophylline Clp or Clm . Antipyrine clearances by EMs and PMs ( Clsal and Clm of 4-OH-antipyrine, 3-OH- methylantipyrine , or norantipyrine) also did not differ. Antipyrine Clsal and Clm correlated to theophylline Clp (r between 0.50 and 0.69). It is concluded that theophylline metabolism (N-demethylations and C-oxidation) is not under the same genetic control as sparteine and debrisoquine oxidations, and that there may be a partial overlap in factors that regulate the metabolism of theophylline and antipyrine.

Adult↗
PubMed1984

Carbamazepine levels in breast milk.

The carbamazepine (CBZ) concentration of breast milk was determined in 19 epileptic patients of whom 13 were receiving CBZ monotherapy. Two lactation periods under CBZ monotherapy were followed in 2 of these 13 patients. The CBZ concentration of the breast milk was 36.4% of the maternal CBZ serum level (mean value). The correlation coefficient was 0.44; the regression line follows the equation y = 0.12X + 1.63. The CBZ concentration was measured in a total of 50 milk samples during the lactation period (cases of monotherapy plus combination therapy). The CBZ concentration ranged from 1 to 4.8 micrograms/ml (mean 2.5 micrograms/ml). The free CBZ concentration in the maternal serum was measured in four patients. The correlation between CBZ in the breast milk and free CBZ levels was 1.6 to 1.8. The ratio of carbamazepine-epoxide (ECBZ) in the milk to ECBZ determined in serum was 0.53. Continuing galactorrhea after delivery was observed in one patient. The CBZ and ECBZ levels determined 3.5 years after delivery were higher in the milk than in the serum. The observations of breast-fed and non-breast-fed children whose mothers were on CBZ monotherapy disclosed poor suckling in only 1 of 15 infants.

Adult↗
PubMed1984

Pharmacokinetics of (+)-, (-)- and (+/-)-verapamil after intravenous administration.

The pharmacokinetics of (+)-, (-)-, and (+/-)-verapamil were studied in five healthy volunteers following i.v. administration of the drugs. Pronounced differences of the various pharmacokinetic parameters were observed between the (-)- and (+)-isomers. The values for CL, V, Vz, and Vss of the (-)-isomer were substantially higher as compared to the (+)-isomer, whereas terminal t 1/ 2Z was nearly identical for both isomers. No dose dependency of the pharmacokinetics could be observed in two subjects who received 5, 7.5 and 10 mg of (-)- and 5, 25 and 50 mg of (+)-verapamil. Protein binding for the two isomers was also different. The fu of (-)- (0.11) was almost twice as much as that of (+)-verapamil (0.064). Pharmacokinetic parameters of (+/-)-verapamil, which was administered to three subjects who had received (+)- and (-)-verapamil, were very similar to the averaged values of the isomers given separately. Due to the higher CL of (-)-verapamil the extraction ratio of the (-)-isomer is substantially higher. Thus, it can be anticipated that following oral administration of racemic verapamil bioavailability of (-)-verapamil will be substantially less. Since the (-)-isomer is more potent than the (+)-isomer, the present findings could explain the reported differences in the concentration-effect relationship after i.v. and oral administration of racemic verapamil.

Adult↗