Search PubMed⌕ Search

Biomedical subjects

M Eichelbaum

Publications and source records attributed to M Eichelbaum.

At least 199 records · Page 11Linked to original sources
PubMed1984

Stereoselective first-pass metabolism of highly cleared drugs: studies of the bioavailability of L- and D-verapamil examined with a stable isotope technique.

The pharmacokinetics of dextro(+)- and levo(-)-verapamil were studied in five healthy volunteers following oral administration of pseudoracemic verapamil containing equal amounts of unlabelled (-)- and dideuterated (+)-isomer. (+)-verapamil exhibited approximately five times greater Cmax (+): 240 +/- 81.1 ng/ml, (-): 46.1 +/- 15.7 ng/ml, P less than 0.0001) and AUC than (-)-verapamil. The apparent oral clearance (CLo) for (+)-verapamil was significantly smaller than that for (-)-verapamil (+): 1.72 +/- 0.57 l/min, (-): 7.46 +/- 2.16 l/min, P less than 0.001). The bioavailability of (+)-verapamil (50%) was 2.5 times greater than that of (-)-verapamil (20%), P less than 0.005). Thus following oral administration verapamil exhibited a stereoselective first-pass metabolism. Neither tmax nor the elimination t1/2,z were different between the isomers. The elimination of t1/2,z for each verapamil isomer obtained following oral administration (+): 4.03 h, (-): 5.38 h) were similar to those previously obtained following intravenous administration (+): 4.15 h, (-): 5.38 h, respectively. Whereas the (+)- to (-)-verapamil plasma concentration ratio following oral administration was 4.92 +/- 0.48, the ratio following i.v. administration was approximately 2. (-)-verapamil has been demonstrated to possess 8 to 10 times more potent negative dromotropic effect on AV conduction than (+)-verapamil. Therefore, following oral administration the same concentration of plasma verapamil consisting of a two to three times smaller proportion of the more potent (-)-isomer appeared to be less potent than that following i.v. administration with regard to the negative dromotropic effects on the AV conduction.

Adult↗
PubMed1984

Clinical pharmacology of calcium antagonists: a critical review.

Although diltiazem, nifedipine, and verapamil exhibit great diversity in chemical structure, they exhibit common pharmacokinetic properties. They are all highly cleared drugs and thus subject to a significant hepatic first-pass metabolism. Therefore, their bioavailability is low despite their almost complete absorption following oral administration. In addition, the bioavailability of these drugs is subject to inter- and intraindividual variations even in healthy subjects. In patients with liver disease, bioavailability increases substantially due to intra- and extrahepatic shunting. During multiple dosing, the oral clearance decreases and bioavailability increases, thus leading to higher steady-state concentrations than those predicted from single-dose studies. The interpretation of pharmacodynamic data in relation to plasma drug concentrations should consider the following points: presence of hysteresis effect and pharmacodynamic models employed for the analysis of the concentration-effect relationship (log-linear versus Emax model). The route of administration can influence the concentration-effect relationship due to the formation of active metabolites and/or stereoselective first-pass metabolism. The available pharmacokinetic data for the three calcium antagonists are discussed with special emphasis on their contribution to pharmacodynamic effects.

Administration, Oral↗
PubMed1983

Antipyrine metabolism in relation to polymorphic oxidations of sparteine and debrisoquine.

Thirty-five healthy subjects who had been classified as extensive or poor metabolizers of both sparteine and debrisoquine were given a single oral dose of antipyrine. Saliva concentration of antipyrine and urinary excretion of its three major oxidation metabolites were measured. All the parameters of antipyrine metabolism which were estimated had similar distributions in both the 28 EM and 7 PM genetic phenotypes defined by the metabolism of sparteine and debrisoquine. The clearance of antipyrine by the formation of 4-hydroxy-antipyrine and 3-hydroxy-antipyrine respectively were closely correlated (r = 0.83, P less than 0.001) and both were significantly higher in smokers than in non-smokers. Demethylation of antipyrine also seemed to be influenced by smoking, but not to a statistically significant extent. These findings confirm the influence of the environmental factor of smoking in antipyrine oxidative biotransformations.

Adult↗
PubMed1982

[Incidence of hepatotoxic side effects during antituberculous therapy (INH, RMP, EMB) in relation to the acetylator phenotype (author's transl)].

In 95 patients with active tuberculosis, we investigated in a prospective study the influence of the acetylator phenotype on the hepatotoxic side effects of the antituberculous regimen isoniazid (INH) 10 mg/kg, rifampicin (RMP) 10 mg/kg, and ethambutol (EMB) 25 mg/kg. Besides a much higher incidence of isoniazid hepatitis (SGOT, SGPT greater than 200 U/l) in 12.6% of patients treated--as compared to the incidence reported in large chemoprophylaxis trials with isoniazid monotherapy in the range of 0.5%-1% (IUAT 1969, U.S.P.H.S. 1971)--we observed a significant, higher risk of isoniazid-induced hepatotoxicity in slow acetylators (p less than 0.01): in 26 of 56 slow acetylators (= 46.4%), but only in 4 of 30 rapid acetylators (=13.3%) were transaminases in the serum elevated greater than 50 U/l. The 12 patients with the most severe hepatotoxic side effects (SGOT, SGPT greater than 200 U/l) were all slow acetylators. Women developed severe hepatic injury more often than men (p less than 0.05). In cases with isoniazid hepatitis, triple therapy was either stopped or reduced to a combination RMP, EMB. In cases with less severe liver injury, triple therapy was continued. In all patients transaminases normalized within 2-4 weeks. On return to full triple therapy, none of the patients developed new elevation of transaminases. The constant occurrence of isoniazid hepatitis during the 2nd-4th week (19 +/- 7 days) as well as the normalization without any new hepatotoxic reaction suggest that there may be an interaction between RMP and isoniazid metabolism limited to the early phase of chemotherapy.

Acetylation↗
PubMed1982

Use of stable labelled carbamazepine to study its kinetics during chronic carbamazepine treatment.

The kinetics of carbamazepine using stable labelled 15N-carbamazepine was studied in 4 epileptic patients who had been treated with it for at least 6 months. There was a decrease in half-life (12.3 +/- 0.8 h) and an increase in total plasma clearance (58.0 +/- 6.5 ml/min) as compared to single dose studies, which provide further evidence that carbamazepine induces its own metabolism during long-term treatment. Analysis of the urinary metabolites indicated induction of the epoxide-trans-diol pathway. Predicted and observed steady-state plasma levels were in good agreement, thus demonstrating that the use of stable labelled drugs is a useful technique to elucidate changes in kinetics and metabolism which may occur in patients during long-term treatment.

Administration, Oral↗
PubMed1982

Prediction of bioavailability for drugs with a high first-pass effect using oral clearance data.

For drugs with a high hepatic clearance, bioavailability is low due to the so-called "first pass effect". Prediction of the bioavailability for these drugs has been only loosely tested. It is proposed that by plotting the reciprocal of bioavailability versus the oral clearance, a straight line with intercept of unity and slope of reciprocal of hepatic blood flow should ensue. For lignocaine and verapamil, this relationship was found to be strong and gave good predictability, whereas for propranolol this relationship was weak and gave poor predictability. The proposed method may be of value in determining whether the low bioavailability of a drug is due to hepatic first pass metabolism.

Administration, Oral↗
PubMed1982

Polymorphic oxidation of sparteine and debrisoquine: related pharmacogenetic entities.

Thirty-eight healthy subjects were given single oral doses of debrisoquine and sparteine in a crossover study. The close correlation between urinary metabolic ratios of the two drugs (rs = 0.91; P less than 0.001) demonstrates that the polymorphic N-oxidation of sparteine and 4-hydroxylation of debrisoquine are related pharmacogenetic entities; the metabolism of the two drugs is regulated by identical or closely related genetic factors.

Adult↗
PubMed1982

Pharmacokinetics and metabolism of antipyrine (phenazone) after intravenous and oral administration.

To 12 healthy male volunteers, 6 smokers and 6 non-smokers, 10 mg/kg antipyrine (phenazone) was administered i.v. and p.o. in random order. Following i.v. administration, antipyrine kinetics could be described best by an open two-compartment model. Absolute bioavailability of an aqueous solution of antipyrine was on average 97%. Antipyrine half-life in smokers was significantly shorter (mean 9.7 h) as compared to non-smokers (mean 11.7 h). Smokers excreted significantly more 3-hydroxymethyl-antipyrine (17.2 +/- 2.4 vs. 14.2 +/- 1.9%) than non-smokers, and clearance to this metabolite was significantly increased in smokers. In addition, cumulative urinary excretion of 4-hydroxy-antipyrine, norantipyrine and 3-hydroxymethyl-antipyrine was on average higher in smokers (77.1 +/- 5.0%) as compared to non-smokers (69.5 +/- 10.8%). Thus, 3-hydroxymethyl-antipyrine formation is induced in smokers.

Administration, Oral↗
PubMed1981

A prospective randomised trial on the effect of monitoring plasma anticonvulsant levels in epilepsy.

To evaluated whether knowledge of plasma levels of anti-epileptic drugs has an effect on therapeutic outcome, 127 epileptic outpatients were randomly assigned to two groups (A and B). Plasma levels of group A were reported to the treating physician who attempted to keep the plasma levels within the "therapeutic range." The treating physician was not informed of the results of plasma level determinations of group B. Data from 105 patients were available for assessment at the end of the study year. Therapeutic results of groups A and B were not significantly different. The reduction in seizure frequency was associated with an increase in plasma concentrations of the anti-epileptic drugs. Thus, under the conditions of the study, knowledge of plasma levels of anti-epileptic drugs did not further improve therapeutic results.

Anticonvulsants↗
PubMed1981

Superiority of stable isotope techniques in the assessment of the bioavailability of drugs undergoing extensive first pass elimination. Studies of the relative bioavailability of verapamil tablets.

Although the absorption of verapamil is almost complete after oral administration, its bioavailability is low due to extensive hepatic first-pass metabolism. Besides large interindividual differences in first-pass metabolism, pronounced day-to-day intraindividual variations in first-pass metabolism are observed, leading to erroneous results in relative bioavailability studies. Stable isotope techniques, which permit simultaneous administration of a solution and a tablet, can successfully be used to overcome these difficulties. The method has the advantage that two experiments can be carried out in a single test. Furthermore, the number of subjects required in bioavailability studies can be greatly reduced. Using this technique the bioavailability of verapamil tablets (Isoptin 80) relative to a stable labelled solution of verapamil was found to be 108.1%, with a 95% confidence interval between 89.1 and 127.1%.

Adult↗
PubMed1981

Simultaneous determination of the intravenous and oral pharmacokinetic parameters of D,L-verapamil using stable isotope-labelled verapamil.

Following i.v. administration, the plasma concentration-time curve of verapamil could best be described by either a mono- or biexponential equation. Total plasma clearance (1.26 1/min) approached liver blood flow (1.51/min), so it can be concluded that its clearance is liver blood flow-dependent. Although absorption was almost complete after oral administration, absolute bioavailability (20%) was low, due to extensive hepatic first-pass metabolism. The approach using stable isotope-labelled and unlabelled drug permits simultaneous administration by the intravascular and extravascular routes, thus allowing determination of absolute bioavailability in a single experiment.

Administration, Oral↗