Enantiomer/enantiomer interaction of (S)- and (R)-propafenone for cytochrome P450IID6-catalyzed 5-hydroxylation: in vitro evaluation of the mechanism.

Many drugs are used as racemates, and the enantiomers may differ in terms of pharmacological properties and disposition. Stereoselective disposition of the enantiomers can arise from metabolism of the enantiomers via different routes catalyzed by different enzymes. In contrast, the enantiomers may be metabolized by the same enzyme at different rates.

Regioselectivity and stereoselectivity of the metabolism of the chiral quinolizidine alkaloids sparteine and pachycarpine in the rat.

1. The metabolism of (-)-sparteine and (+)-sparteine (pachycarpine) was investigated in male Sprague-Dawley rats by g.l.

Metabolism of verapamil in a family pedigree with deficient N-oxidation of trimethylamine.

The oxidative N-dealkylation of verapamil has been studied in a family of five members with two propositi with an inherited deficiency of trimethylamine N-oxidation (fish-odour syndrome). The results were assessed for possible co-segregation of the trimethylamine N-oxidation phenotype and any observed deficiency in oxidative N-dealkylation. The general pattern of metabolism of verapamil in the five subjects studied was similar to that reported in earlier investigations.

Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism.

The debrisoquine/sparteine polymorphism is associated with a clinically important genetic deficiency of oxidative drug metabolism. From 5% to 10% of Caucasians designated as poor metabolizers (PMs) of the debrisoquine/sparteine polymorphism have a severely impaired capacity to metabolize more than 25 therapeutically used drugs. The impaired drug metabolism in PMs is due to the absence of cytochrome P450IID6 protein.

Pharmacokinetics, bioavailability, metabolism and acute and chronic antihypertensive effects of nitrendipine in patients with chronic renal failure and moderate to severe hypertension.

1. The pharmacokinetics, bioavailability, metabolism and antihypertensive effects of nitrendipine have been studied in 12 patients with impaired renal function and moderate to severe hypertension. The drug was administered simultaneously by the i.

Codeine O-demethylation: rat strain differences and the effects of inhibitors.

The oxidative metabolism of more than 20 drugs (e.g. sparteine, debrisoquine, dextromethorphan) is mediated by cytochrome P450IID6.

Effects of verapamil enantiomers and major metabolites on the cytotoxicity of vincristine and daunomycin in human lymphoma cell lines.

Verapamil, a calcium channel blocker, is used as the racemate. Recently, racemic verapamil has been shown to increase the cytotoxicity of vinca alkaloid and anthracycline derivatives in several resistant tumour cell lines. With respect to its cardiovascular activity S-verapamil is an order of magnitude more potent than R-verapamil.

Polymorphic flecainide disposition under conditions of uncontrolled urine flow and pH.

The pharmacokinetics of R- and S-flecainide have been determined in five poor (PM) and five extensive (EM) metabolisers of sparteine/debrisoquine under conditions of uncontrolled urine flow and pH. The half-lives of R- and S-flecainide in PMs (R 19.3 h; S 16.

Acute haemodynamic effects of i.v. nitrendipine in healthy subjects.

The haemodynamic effects of an i.v. infusion of 2 mg nitrendipine have been studied in six healthy volunteers.

Identification of thiodiglycolic acid, thiodiglycolic acid sulfoxide, and (3-carboxymethylthio)lactic acid as major human biotransformation products of S-carboxymethyl-L-cysteine.

S-Carboxymethyl-L-cysteine (CMC) is used both as an orally administered mucolytic agent and as a probe drug for uncovering polymorphic sulfoxidation of other sulfur-containing drugs in humans. However, several recent studies could not confirm the formation of significant amounts of urinary sulfoxides of CMC or its decarboxylation product S-methyl-L-cysteine. The metabolism of CMC and a 13C-labeled isotopomer was therefore reinvestigated in 11 and 14 humans, respectively, and emphasis was laid on monitoring of potential alternative metabolic pathways.

Identification of the primary gene defect at the cytochrome P450 CYP2D locus.

The mammalian cytochrome P450-dependent monooxygenase system is involved in the metabolism of drugs and chemical carcinogens. The role of these enzymes in toxicological response is exemplified by an autosomal recessive polymorphism at the cytochrome P450 CYP2D6 debrisoquine hydroxylase locus which results in the severely compromised metabolism of at least 25 drugs, and which in some cases can lead to life-threatening side-effects. In addition, this polymorphism, which affects 8-10% of the caucasian population, has been associated with altered susceptibility to lung and bladder cancer.

Patients with type II autoimmune hepatitis express functionally intact cytochrome P-450 db1 that is inhibited by LKM-1 autoantibodies in vitro but not in vivo.

Liver-kidney microsomal-1 autoantibodies characterize a subgroup of autoimmune chronic active hepatitis. The liver antigen of liver-kidney microsomal-1 antibodies has been identified as cytochrome P450 db1, a microsomal enzyme catalyzing the oxidative metabolism of more than 20 drugs, including debrisoquine, sparteine and bufuralol. A genetic polymorphism (debrisoquin-sparteine polymorphism) is responsible for the lack of P450 db1 protein in the livers of 5% to 10% of Caucasians, leading to impaired drug metabolism and a distinct poor metabolizer phenotype.

Interaction of verapamil and cimetidine: stereochemical aspects of drug metabolism, drug disposition and drug action.

The pharmacokinetics, metabolism and pharmacodynamics of verapamil (160 mg p.o. of a pseudoracemic mixture) were evaluated in six healthy volunteers before and after coadministration of cimetidine (400 mg b.

Acetylation pharmacogenetics. The slow acetylator phenotype is caused by decreased or absent arylamine N-acetyltransferase in human liver.

The biochemical basis underlying the genetic polymorphism of drug N-acetylation was investigated using a combination of in vivo and in vitro assays for arylamine N-acetyltransferase (NAT) activity and content in human liver. The acetylator phenotype of 26 surgical patients was determined using caffeine as an innocuous probe drug by measurement of the 5-acetyl-amino-6-formylamino-3-methyluracil to 1-methylxanthine molar ratio in urine. Liver wedge biopsies from these patients and livers from 24 organ donors were then used for measurement of N-acetyltransferase activity with the substrate sulfamethazine and for quantitation of immunoreactive N-acetyl-transferase protein.

The teaching and organisation of clinical pharmacology in European medical schools (W.H.O. Working Group on Clinical Pharmacology).

A World Health Organisation (European Regional Office) working party has been established to review the progress of clinical pharmacology in European countries. As part of this review a questionnaire on the teaching of clinical pharmacology was sent to the Deans of all 350 medical schools in the region. Very few replies were received from U.

The genetic polymorphism of debrisoquine/sparteine metabolism--clinical aspects.

It has been established that the metabolism of more than twenty drugs, including antiarrhythmics, beta-adrenoceptor antagonists, antidepressants, opiates and neuroleptics is catalyzed by cytochrome P-450dbl. The activity of this P-450 isozyme is under genetic rather than environmental control. This article discusses the therapeutic implications for each of the classes of drugs affected by this genetic polymorphism in drug metabolism.

Effects of verapamil on anthracycline-induced cardiomyopathy: preliminary results of a prospective multicenter trial.

Previous investigations in animals and one retrospective study in man suggest that verapamil can prevent anthracycline-induced cardiomyopathy. In the following study, patients with acute myeloid leukemia (AML) treated with double induction and consolidation chemotherapy (AML COOP study 1986, [3]) were randomized in a group with and without accompanying low-dose oral verapamil treatment. Since July 1986, 64 patients have been included.

Stereoselective disposition of flecainide in relation to the sparteine/debrisoquine metaboliser phenotype.

1. The disposition of the enantiomers of the antiarrhythmic drug flecainide has been studied in five extensive (EM) and five poor (PM) metabolisers of sparteine/debrisoquine after administration of 50 mg of racemic flecainide acetate under conditions of high urinary flow rate and acidic urinary pH. 2.

[Stereospecific hydroxylation of (+)-sparteine (pachycarpine) in the rat].

Pachycarpine (4), the optical antipode of the lupine alkaloid (-)-sparteine (1), has been prepared from (-)-lupanine; its metabolism was studied in rats. After isolation and chromatographic purification, streochemically homogeneous (+)-(4S)-hydroxysparteine (7) was identified as the major urinary metabolite by use of mass spectrometry and high-field NMR-spectroscopy.

Stereoselective disposition and pharmacologic activity of propafenone enantiomers.

Propafenone is an antiarrhythmic drug that produces a variable degree of beta-blockade in humans and is administered as a racemate. To examine the relative contribution of the individual enantiomers to pharmacologic effects seen during treatment with propafenone, we assessed the steady-state plasma concentrations of (+)-S-propafenone and (-)-R-propafenone in seven patients who were on long-term oral therapy, and we evaluated the electrophysiologic and beta-blocking properties of both enantiomers in vitro. The metabolism of propafenone is known to be polymorphic and to cosegregate with that of debrisoquine-4-hydroxylation.

The influence of the sparteine/debrisoquin phenotype on the disposition of flecainide.

The pharmacokinetics and urinary excretion of flecainide (50 mg administered orally) were investigated in five extensive metabolizers (EMs) and five poor metabolizers (PMs) of the sparteine/debrisoquin type of polymorphism under conditions of controlled urinary pH. Flecainide disposition was altered in the PMs. The AUC was higher (1462 +/- 407 versus 860 +/- 256 hr ng/ml), the elimination half-life prolonged (11.

In vitro characterization of the human cytochrome P-450 involved in polymorphic oxidation of propafenone.

Propafenone is a new class 1 antiarrhythmic agent. The drug is extensively metabolized. 5-Hydroxylation and N-dealkylation constitute major metabolic pathways.