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H K Kroemer

Publications and source records attributed to H K Kroemer.

16 recordsLinked to original sources
PubMed1992

Genetically determined differences in drug metabolism as a risk factor in drug toxicity.

Drug metabolizing enzymes are of paramount importance in drug detoxification as well as chemical mutagenesis, carcinogenesis and toxicity via metabolic activation. Thus genetically determined differences in the activity of these enzymes can influence individual susceptibility to adverse drug reactions, drug induced diseases and certain types of chemically induced cancers. The genetic polymorphisms of three human drug metabolizing enzymes, namely N-acetyltransferase and two cytochrome P-450 isozymes (P-4502D6: debrisoquine/sparteine polymorphism, P-4502C8-10: mephenytoin polymorphism) have been firmly established. Based on the metabolic handling of certain probe drugs, the population can be divided into two phenotypes: the rapid acetylator/extensive metabolizer and slow acetylator/poor metabolizer. These polymorphisms have provided useful tools to study the relationship between genetically determined differences in the activity of drug metabolizing enzymes and the risk for adverse drug reactions and certain types of chemically-induced diseases and cancers. With regard to the susceptibility of the two phenotypes, drug mediated toxicity for the following scenarios can be anticipated. (1) The toxicity of the drug is caused by the parent compound and the elimination of the drug proceeds exclusively via the polymorphic enzyme. No alternate pathways of biotransformation are available. Thus the slow acetylator/poor metabolizer phenotype will be more prone to such a type of toxicity since, at the same level of exposure, this phenotype will accumulate the drug as a result of impaired metabolism (e.g. isoniazid polyneuropathy, perhexiline polyneuropathy, pesticide induced Parkinsons disease). (2) The polymorphic pathway is a major route of detoxification. Impairment of this pathway shifts the metabolism to an alternate pathway via which a reactive intermediate is being formed. In such a situation the slow acetylator/poor metabolizer phenotype constitutes a major risk factor for toxicity (e.g. isoniazid hepatotoxicity). (3) The toxicity is mediated by a reactive intermediate generated by a polymorphic enzyme. Hence extensive metabolizers are at a much higher risk than poor metabolizers to develop toxicity or cancer (e.g. bronchial carcinoma in smokers, not chemically induced aggressive bladder cancer).

Animals↗
PubMed1992

Glucuronidation of drugs. A re-evaluation of the pharmacological significance of the conjugates and modulating factors.

Glucuronides of drugs are considered to be generally inactive and rapidly eliminated. Therefore, these metabolites are often not taken into account in evaluating drug effects. The present review describes examples of both direct and indirect contributions of glucuronides to net drug effects. Multiple lines of evidence indicate that morphine-6-glucuronide has analgesic activity. This compound has a high affinity to the mu-receptor, is capable of penetrating the blood/brain barrier and is a potent analgesic after administration to patients. Indirect activity of glucuronides may consist of a systemic cycle in which an active parent compound is derived from the glucuronide by enzymatic action. Such systemic cycling has been demonstrated for clofibric acid. In addition, some acyl glucuronides are subject to intramolecular rearrangement and the resulting metabolites are resistant to beta-glucuronidase. Covalent protein binding of glucuronides by different mechanisms may contribute to drug toxicity and immune responses. If glucuronides are accepted as potential modifiers of net drug action it is important to determine what factors modulate disposition of these compounds. Therefore, the later section of this review describes glucuronidation under different pathophysiological conditions. Examples for alterations of the rate and/or extent of glucuronidation by concurrent diseases processes, age and coadministration of other drugs are provided.

Age Factors↗
PubMed1992

Predictability of the in vivo metabolism of verapamil from in vitro data: contribution of individual metabolic pathways and stereoselective aspects.

In vitro studies of drug metabolism with human liver microsomes can be performed in the early stages of drug development. Such experiments may reflect the in vivo metabolism of drugs in humans and thus allow for a prediction of drug disposition before the compound is administered to humans. We tested this hypothesis for the example of verapamil, which is a calcium channel blocker that undergoes extensive metabolism. Moreover, the drug is administered as a racemate, and stereoselective first-pass metabolism favoring the extraction of the more potent S-verapamil is observed after p.o. administration. To evaluate the in vitro metabolism, microsomes prepared from 10 human livers were incubated with both S- and R-verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

The drug interaction potential of ranitidine: an update.

Ranitidine is a H2-receptor antagonist widely used in the treatment of a variety of gastrointestinal disorders. Since cimetidine--the predecessor drug of ranitidine--interacts with a variety of other agents and moreover ranitidine is often administered in combination with other drugs the interaction potential of ranitidine has been subject to extensive investigations. This review updates the information available from 1988 to present. Pharmacokinetic interactions of ranitidine with other drugs may occur at the site of absorption, metabolism and renal excretion. Most of the interactions reported at each of the three levels are minor and of low clinical significance. In view of some uncontrolled anecdotal reports, one cannot completely rule out the possibility that ranitidine might have some limited interaction potential in special patient populations under certain clinical conditions. However, it must be emphasized that numerous controlled studies have proven that ranitidine can be safely coadministered with other drugs.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1991

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. In the latter case, the enantiomers can compete for this metabolic step, giving rise to the possibility of an enantiomer/enantiomer interaction. We have chosen the antiarrhythmic propafenone, for which in vivo data indicated an interaction between (S)- and (R)-propafenone, as a model substance to study the mechanism underlying that interaction in human liver microsomes. We used the cytochrome P450IID6-mediated 5-hydroxylation of propafenone as a model pathway, because this metabolic step constitutes the major route of biotransformation of propafenone. The Michaelis-Menten kinetics for 5-hydroxylation were determined after incubation of (R)- and (S)-propafenone and a pseudoracemate consisting of (S)-[2H4]propafenone and (R)-propafenone. Inhibition experiments were performed using (S)-[2H4]propafenone as an inhibitor of the 5-hydroxylation of (R)-propafenone, and vice versa. The kinetic model of mixed alternative substrates was used to simulate inhibition experiments. Experimental data were compared with those predicted by this model. We observed a substantial stereoselectivity after incubation of the individual enantiomers [(S)-propafenone: Vmax, 10.2 pmol/micrograms/hr, and Km, 5.3 microM; (R)-propafenone: Vmax, 5.5 pmol/micrograms/hr, and Km, 3.0 microM]. In contrast, no substrate stereoselectivity was observed after incubation of the pseudoracemate [3.1 pmol/micrograms/hr for (S)-[2H4]propafenone and 3.3 pmol/micrograms/hr for (R)-propafenone]. Application of the model revealed Ki values of 2.9 and 5.2 microM for the inhibition of 5-hydroxylation of (S)-[2H4]-propafenone by (R)-propafenone and for inhibition of 5-hydroxylation of (R)-propafenone by (S)-[2H4]-propafenone, respectively. The predicted and the experimental data were in good agreement, and both indicated the mode of inhibition to be competitive. In conclusion, the enantiomers of propafenone interact with respect to 5-hydroxylation, with (R)-propafenone being a more potent inhibitor than the S-enantiomer with respect to cytochrome P450IID6-mediated 5-hydroxylation. Because beta-blocking properties of propafenone reside in the S-enantiomer, inhibition of metabolism of this enantiomer by (R)-propafenone may have therapeutic consequences.

Adolescent↗
PubMed1991

Influence of debrisoquine phenotype and of quinidine on mexiletine disposition in man.

Mexiletine is a low clearance drug which undergoes extensive metabolism in man. In vitro studies with human liver microsomes have suggested that major oxidation pathways of mexiletine are predominantly catalyzed by the genetically determined debrisoquine 4-hydroxylase (cytochrome P450IID6) activity. In this study, we investigated the role of debrisoquine polymorphism and the effects of low dose quinidine, a selective inhibitor of cytochrome P450IID6, on the disposition of mexiletine. Fourteen healthy volunteers, 10 with the extensive metabolizer (EM) and 4 with the poor metabolizer (PM) phenotype, received a single 200-mg dose of mexiletine hydrochloride orally on two occasions (1 week apart), once alone and once under steady-state conditions for quinidine (50 mg QID). During the phase mexiletine alone, total clearance, nonrenal clearance and partial metabolic clearance of mexiletine to hydroxymethylmexiletine, to m-hydroxymexiletine and to p-hydroxymexiletine were decreased in PM compared to EM (all P less than .05). In EM, quinidine decreased mexiletine total clearance from 621 +/- 298 to 471 +/- 214 ml/min (mean +/- S.D.; P less than .05) and mexiletine nonrenal clearance from 583 +/- 292 to 404 +/- 188 ml/min (P less than .05). Moreover, quinidine increased mexiletine elimination half-life in EM from 9 +/- 1 to 11 +/- 2 h (P less than .05). In these subjects, partial metabolic clearance to hydroxymethylmexiletine, m-hydroxymexiletine and p-hydroxymexiletine were decreased by quinidine coadministration 5-, 4- and 7-fold, respectively, whereas partial metabolic clearance to N-hydroxymexiletine was unaffected. Changes induced by quinidine in EM were correlated to their debrisoquine metabolic ratio. Thus, genetically determined or pharmacologically induced modulation of cytochrome P450IID6 activity represents a major determinant of mexiletine disposition.

Administration, Oral↗
PubMed1990

The role of genetically determined polymorphic drug metabolism in the beta-blockade produced by propafenone.

Propranolol and the sodium-channel-blocking antiarrhythmic agent propafenone share structural features. Although propafenone's beta-blocking actions are readily demonstrable in vitro, clinically significant beta-blockade occurs inconsistently in vivo. In this study, we tested the hypothesis that genetically determined variations in the biotransformation of propafenone to its 5-hydroxy metabolite account for variations in the drug's beta-blocking action. We assessed beta-blockade by measuring the reduction in tachycardia produced by boluses of isoproterenol and treadmill exercise in 14 normal subjects during treatment with placebo and with 150, 225, and 300 mg of propafenone every eight hours for five days each. Nine subjects (with the extensive-metabolizer phenotype) metabolized most of the propafenone to 5-hydroxy propafenone, and five (with the poor-metabolizer phenotype) did not produce this metabolite. At the lower dosages, beta-blockade was present in both groups but was significantly greater in the subjects with poor metabolism, in whom deficient 5-hydroxylation was associated with higher plasma propafenone levels. At the highest dose, a similar degree of beta-blockade was observed in the two groups. Propafenone also had a higher affinity for beta 2 receptors in vitro than either of its major metabolites. We conclude that the degree of beta-blockade during propafenone therapy reflects genetically determined variations in the metabolism of the parent drug, which is necessary for beta-blockade, and that this action of propafenone is considerably enhanced in patients with deficient 5-hydroxylation of propafenone.

Adrenergic beta-Antagonists↗
PubMed1990

Propafenone.

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Arrhythmias, Cardiac↗
PubMed1990

Stereoselective determination of flecainide in human plasma by high-performance liquid chromatography with fluorescence detection.

Enantiomers of a drug may differ in their pharmacological activities or their disposition constants. We now describe a stereoselective analytical method for the determination of the antiarrhythmic agent flecainide in plasma. The resolution of the enantiomers is achieved by high-performance liquid chromatography (HPLC) on a normal phase silica column following derivatization with the optically active reagent (-)-methyl chloroformate. The eluting diastereoisomers are monitored by fluorescence detection at an excitation wavelength of 305 nm and an emission wavelength of 340 nm. The limit of sensitivity for the assay is as low as 2.5 ng/mL for each enantiomer using 1 mL of plasma. A new liquid-liquid extraction procedure with high recovery (greater than 95%) and high selectivity is also reported. The intra- and interassay coefficient of variation for replicated analysis of spiked plasma samples is less than 4.0% and 7.0%, respectively. The method is suitable for single and multiple dose pharmacokinetic studies in healthy volunteers or in patients.

Chromatography, High Pressure Liquid↗
PubMed1990

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.i.d.). Enantiomers of verapamil and enantiomers of three major urinary metabolites (norverapamil, D-617 and D-620) were determined in plasma and urine by gas chromatography-mass spectrometry. Coadministration of cimetidine led to a significant increase in the area under the plasma concentration vs. time curve of S-verapamil (29.2 +/- 31.8 min x nmol x ml-1 vs. 41.2 +/- 33.7 min x nmol x ml-1; P less than .003) and R-verapamil (124.7 +/- 112.2 min x nmol x ml-1 vs. 156.8 +/- 105.0 min x nmol x ml-1; P less than .01). The increase was significantly greater for the pharmacologically more potent S-enantiomer compared to R-verapamil (150.3 +/- 37 vs. 117.8 +/- 15%; P less than .05). As a consequence, coadministration of cimetidine increased the negative dromotropic effect of verapamil on atrioventricular conduction in five of six subjects. In addition, fractional metabolic clearance to D-620 and D-617 decreased for both enantiomers. Tubular secretion of S-D-617 was inhibited by cimetidine (342 +/- 104 vs. 238 +/- 52 ml x min-1; P less than .05) whereas secretion of the R-enantiomer remained unchanged (276 +/- 91 vs. 222 +/- 43 ml x min-1). Thus, cimetidine interacts with both hepatic and renal verapamil elimination in a stereoselective manner. The increase in total plasma concentration of verapamil combined with an increase in eutomer/distomer ratio produces a more pronounced pharmacological effect of verapamil when cimetidine is coadministered.

Administration, Oral↗
PubMed1989

Flecainide enantiomers: disposition in human subjects and electrophysiologic actions in vitro.

The antiarrhythmic agent flecainide is administered as a racemate. The disposition of the individual enantiomers and their electrophysiologic actions are unknown. We therefore determined through plasma levels of S-(+)-flecainide and R-(-)-flecainide in 13 patients who were receiving long-term oral flecainide therapy. In addition, the effects of the enantiomers on action potential characteristics in canine cardiac Purkinje fibers were assessed. Plasma concentrations of R-(-)flecainide were significantly higher than those of the S-(+)-enantiomer (-/+ ratio, 1.10 +/- 0.13,mean +/- SD; range, 0.89 to 1.32, p less than 0.01), suggesting that the drug undergoes enantioselective disposition. In the in vitro experiments, both enantiomers reduced phase 0 action potential Vmax (an index of the fast inward sodium current) and shortened action potential duration at 50% and 90% repolarization, but no differences between the enantiomers were detected. The time constants for development of Vmax depression were significantly longer for S-(+)-flecainide (13.4 +/- 1.5 seconds) compared with R-(-)-flecainide (8.9 +/- 0.6 seconds, p less than 0.001). Thus, although S-(+)-flecainide and R-(-)-flecainide undergo modest enantioselective disposition, they exert similar electrophysiologic effects. These studies have provided no evidence to indicate that administration of a single enantiomer, rather that the racemic drug, would offer any advantage.

Action Potentials↗
PubMed1989

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. Recently it has been demonstrated that the in vivo metabolism of propafenone is controlled by the debrisoquin/sparteine polymorphism. To elucidate which of the above metabolic reactions is catalyzed by cytochrome P-450db1, the formation of 5-hydroxypropafenone and N-desalkylpropafenone was studied in the microsomal fraction of four human kidney donor livers previously characterized with regard to their ability to hydroxylate the beta-adrenergic antagonist bufuralol. The l'hydroxylation of bufuralol is catalyzed by the P-450db1 responsible for polymorphic debrisoquin/sparteine oxidation. The formation of 5-hydroxypropafenone but not N-desalkylpropafenone was closely related to bufuralol l'hydroxylation. Incubation with LKM1 antibodies, which selectively recognize P-450db1, inhibited 5-hydroxypropafenone formation completely whereas N-dealkylation was unimpaired. Propafenone was a strong competitive inhibitor of bufuralol l'hydroxylation. Thus it can be concluded that 5-hydroxypropafenone is formed by the cytochrome P-450 isozyme involved in polymorphic bufuralol oxidation.

Autoantibodies↗
PubMed1989

Genetically-determined interaction between propafenone and low dose quinidine: role of active metabolites in modulating net drug effect.

1. Quinidine is a potent inhibitor of the genetically-determined debrisoquine 4-hydroxylation. Oxidation reactions of several other drugs, including the 5-hydroxylation of the new antiarrhythmic drug propafenone, depend on the isozyme responsible for debrisoquine 4-hydroxylation. 2. The effect of quinidine on the debrisoquine phenotype-dependent 5-hydroxylation and the pharmacological activity of propafenone was studied in seven 'extensive' metabolizers and two 'poor' metabolizers of the drug receiving propafenone for the treatment of ventricular arrhythmias. 3. In patients with the extensive metabolizer phenotype, quinidine increased mean steady-state plasma propafenone concentrations more than two fold, from 408 +/- 351 (mean +/- s.d.) to 1096 +/- 644 ng ml-1 (P less than 0.001), decreased 5-hydroxypropafenone concentrations from 242 +/- 196 to 125 +/- 97 ng ml-1 (P less than 0.02) and reduced propafenone oral clearance by 58 +/- 23%. 4. Despite these changes in plasma concentrations, electrocardiographic intervals and arrhythmia frequency were unaltered by quinidine coadministration, indicating that 5-hydroxypropafenone contributes to the pharmacologic effects of propafenone therapy in extensive metabolizers. 5. In contrasts, plasma concentrations of propafenone and 5-hydroxypropafenone remained unchanged in the two patients with the poor metabolizer phenotype. 6. Biotransformation of substrates for the debrisoquine pathway can be markedly perturbed by even low doses of quinidine; interindividual variability in drug interactions may have a genetic component.

Adult↗
PubMed1989

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. Among five patients with the extensive metabolizer phenotype (EM), the ratio of the area under the plasma concentration-time curve of (+)-S-propafenone to (-)-R-propafenone was 1.73 +/- 0.15 (mean +/- SD). In the other two patients, who had the poor metabolizer phenotype (PM), the concentrations of both enantiomers were elevated but the S/R ratios were similar to those seen in patients with EM. In canine cardiac Purkinje fibers, both enantiomers produced similar frequency-dependent depression of maximum upstroke of phase 0. In contrast, the affinity of the human lymphocyte beta 2-adrenoceptor was approximately 100-fold greater for (+)-S-propafenone (Ki, 7.2 +/- 2.9 nM) than for the (-)-R-enantiomer (Ki, 571 +/- 141 nM). We conclude that during long-term oral therapy, propafenone undergoes stereoselective disposition in patients with either EM or PM. beta-Blockade during propafenone therapy is likely related to accumulation of (+)-S-propafenone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗