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Biomedical subjects

M Eichelbaum

Publications and source records attributed to M Eichelbaum.

At least 217 records · Page 12Linked to original sources
PubMed1981

Pharmacokinetics, bioavailability and ECG response of verapamil in patients with liver cirrhosis.

1 The pharmacokinetics, bioavailability and ECG response of verapamil was investigated in seven patients with liver cirrhosis and compared with six normal subjects, using stable labelled techniques whereby both the intravenous and oral dose are given simultaneously. 2 After intravenous administration, plasma concentrations were much higher in the patient group such that the total plasma clearance was reduced from a mean of 1258 ml/min in normals to 616 ml/min in the patient group (P less than 0.0025). The apparent volume of distribution nearly doubled (6.76 v 12.05 l/kg, P less than 0.025) and the terminal half-life was prolonged four fold (3.7 v 14.2 h, P less than 0.001). 3 Given orally, the peak plasma concentration was higher and occurred earlier in the liver cirrhotic patients. The absolute bioavailability more than doubled (22.0% normals v 52.3% liver cirrhotics, P less than 0.001) and apparent oral clearance was reduced to only 20% of normal (6.38 v 1.30 l/min, P less than 0.001). 4 The delta P-R interval in the patient group lagged behind the plasma concentration, in contrast to normal subjects. The maximum effect was much greater in the patients (15.4 v 41.6% increase, P less than 0.005) and persisted for a longer period of time. The slope of the plasma concentration-response curve was the same as in normals after intravenous administration. Plasma protein binding remained unchanged. 5 It is recommended that in liver cirrhotic patients the intravenous dose of verapamil be halved and the oral dose decreased by a factor of five in order to prevent untoward effects. As well as a steady-state plasma concentration will not be reached until approximately 2 days after the beginning of therapy.

Adult↗
PubMed1981

HPLC determination of antipyrine metabolites.

A high-performance liquid chromatography method is described which allows for the simultaneous determination of antipyrine, 4-hydroxyantipyrine, norantipyrine and 3-hydroxyantipyrine. Hydrolysis conditions with respect to source glucuronidase, amount of glucuronidase, pH of incubation and addition of antioxidant to the incubation medium proved to be very critical for norantipyrine and to a lesser extent 4-hydroxyantipyrine. The method is of good sensitivity, accuracy and reproducibility. Thus, the method is well suited for detailed metabolic studies.

Antioxidants↗
PubMed1981

[Drug dosing in chronic hepatic disease (author's transl)].

Disposition of drugs, which are primarily metabolized by the liver, will be influenced in chronic liver disease by the following factors: intrinsic clearance, liver blood flow, and shunt volume. This group of drugs may be divided in two subgroups: (a) drugs with a high clearance, a high extraction rate and a short biological half-time, and (b) drug with a low clearance, a low extraction rate, and a long biological half-time. A high extraction rate means a low systemic bioavailability, since a rather big proportion of the drug will be eliminated after oral intake already during the first pass through the liver (= first past effect). In liver cirrhosis bioavailability may be increased manifold because of the portosystemic shunting. Thus there is the danger of overdosage in group (a) drugs because of two mechanisms: reduced elimination and increased bioavailability.

Biological Availability↗
PubMed1980

Effects of verapamil on P-R-intervals in relation to verapamil plasma levels following single I.V. and oral administration and during chronic treatment.

A close relationship between verapamil plasma concentration and effect on P-R interval could be established both after single i.v. and oral administration and during chronic oral treatment. After i.v. administration a linear relationship between verapamil plasma concentration and delta P-R (y=x (0.74) + 1.8) with a small between subject variation in the slope of the regression (%coefficient of variation 18.7, range 0.71-1.10) was observed. The slope of the oral plasma concentration response regression (y=x (0.33)-3.0) was statistically significantly (p less than 0.05) less than the slope of the i.v. plasma level response regression. Interindividual variation in the slope was most pronounced (range 0.13 to 0.47). On average two to three times higher verapamil plasma levels were required after oral administration in order to produce the same increase in delta PR as after intravenous administration. The most plausible explanation for the different slopes of the plasma level response regression seems to be stereo-selective presystemic elimination. Since after oral administration the plasma level response curve is less steep than after i.v. administration this indicates that the more active l-isomer is preferentially metabolized during hepatic first-pass metabolism.

Administration, Oral↗
PubMed1980

Pharmacogenetic covariation of defective N-oxidation of sparteine and 4-hydroxylation of debrisoquine.

Two subjects from each of the three groups of homozygous rapid, heterozygous, and homozygous non-metabolizers (N-oxidation) of sparteine received a single oral dose of debrisoquine. The urinary ratio of debrisoquine/4-hydroxy-debrisoquine, reflecting the individual's capacity to C-hydroxylate debrisoquine, was closely related to his phenotype for sparteine metabolism. This indicates that the two metabolic reactions are controlled by similar if not identical genetic factors.

Adult↗
PubMed1980

Mass spectrometric identification of DL-verapamil metabolites.

DL-verapamil [2,8-bis(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile; Isoptin] is metabolized in man by N-dealkylation -- mainly by cleavage of the N6-C7 bond -- and by demethylation of the methoxy groups. After oral administration, besides unchanged verapamil, 12 metabolites could be isolated from urine and their structures were elucidated by (GC-) mass spectrometry.

Biotransformation↗
PubMed1979

Kinetics and metabolism of carbamazepine during combined antiepileptic drug therapy.

The kinetics of carbamazepine using 15N-carbamazepine were investigated in epileptic patients during combined anticonvulsant therapy. The 15N-carbamazepine plasma half-lives ranged from 5.0 to 13.6 hr with a mean of 8.2 hr. These half-lives are appreciably shorter than reported during chronic carbamazepine monotherapy. Predicted steady-state plasma levels and observed plasma levels of carbamazepine were in excellent agreement. Between 32% and 61% of the dose administered is excreted in the urine as carbamazepine-trans-diol, 5.2% to 8.8% as 9-hydroxymethyl-10-carbamoyl acridane, 1% to 1.4% as 10,-11-carbamazepine epoxide, and 0.5% as carbamazepine. The data indicate that it is the epoxide-diol pathway which is induced during long-term treatment. Concomitant therapy with primidone, phenytoin, phenobarbital, ethosuximide, or methsuximide further induces carbamazepine metabolism.

Adult↗
PubMed1979

Defective N-oxidation of sparteine in man: a new pharmacogenetic defect.

Sparteine, an antiarrhythmic and oxytocic drug, is metabolised by N1-oxidation. The sparteine-N1-oxide rearranges with loss of water to 2- and 5-dehydrosparteine. 18 (i.e., 5%) out of 360 subjects were unable to metabolise the drug. These persons, who were designated as nonmetabolisers, excreted almost 100% of the administered dose in urine as unchanged drug. The defective metabolism of sparteine was found to have a genetic basis. Sparteine-N1-oxidation appears to be determined by two allelic genes at a single locus where nonmetabolisers are homozygous for an autosomal recessive gene.

Family↗
PubMed1979

Influence of the defective metabolism of sparteine on its pharmacokinetics.

Sparteine is metabolized by N1-oxidation, which in some subjects is defective. The defect has a pronounced effect on the kinetics of the drug. In nonmetabolisers elimination of sparteine proceeds entirely via renal excretion by a capacity-limited process, 99,9% of the dose being excreted as unchanged drug. In metabolisers the drug is mainly eliminated by metabolic degradation. Pronounced differences in beta-phase half-life and total plasma clearance were observed between metabolisers (156 min; 535 ml . min-1) and nonmetabolisers (409 min; 180 ml . min-1).

Adult↗
PubMed1978

Determination of monoureides in biological fluids by high-pressure-liquid-chromatography.

A sensitive and specific method for the simultaneous determination of bromisoval, carbromal, and methaqualone is described. The drugs are adsorbed from serum onto charcoal at pH 11 and eluted from it with organic solvent. The eluate is separated by high-pressure liquid-chromatography on reverse phase (RP 18) column using acetonitrile: water (26 : 74 by volume) as mobile phase. The eluted drugs are detected by uv-absorption at 210 nm. The method is sensitive, specific, precise, and accurate.

Bromisovalum↗
PubMed1978

[On the metabolism of antipyrine (phenazone) in man (author's transl)].

The metabolism of antipyrine (phenazone) was studied by means of C14-antipyrine labelled at C-3. Besides the metabolites already known two conjugates were isolated and characterized by their mass spectra. The occurrence of 2-hydroxymethyl-3-methyl-1-phenyl-3-pyrazolin-5-one and 3,4-dihydroxy-2,3-dimethyl-1-phenyl-pyrazolidin-5-one could not be confirmed, although 95% of the radioactivity administered was recovered.

Antipyrine↗