Michel Eichelbaum

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

SummarySparteine, 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.

Defective Oxidation of Drugs: Pharmacokinetic and Therapeutic Implications

SummaryUntil quite recently, pharmacogenetic polymorphisms in oxidative drug metabolism were considered rare. However during the last years several monogenically determined poly of oxidative reactions in drug metabolism involving benzylic hydroxylation of debrisoquine, N-oxidation of sparleine, C-hydroxylation of tolbutamide, O-de-ethylation of phenacetin, p-hydroxylation of Phenytoin and mephenytoin and N-glucosidation of amylobarbitone (amobarbital) have been discovered. The incidence of these various pharmacogenetic conditions varies between 2 and 9 % of the population. Among these conditions the best studied examples are the polymorphic oxidation of debrisoquine and sparteine.In population studies it was observed that 4-hydroxylation of debrisoquine and N-oxidation of sparteine, the metabolic processes removing most of the drug from the body, were grossly impaired or nearly absent in some subjects. These subjects were designated poor metabolisers (debrisoquine) or non-metabolisers (sparteine). The frequency of the poor metaboliser phenotype of debrisoquine is 8.9% in the white British population, and the non-metaboliser phenotype of sparteine occurs in 5% of the German population. For both drugs it was demonstrated that 4-hydroxylation of debrisoquine and N-oxidation of sparteine are determined by 2 allelic genes at a single gene locus; thus, poor and non-metabolisers are homozygous for an autosomal recessive gene. These defects cause changes in the pharmacokinetics and bioavailability of both drugs, thereby enhancing their pharmacological effects. Poor and non-metaboliser subjects are at higher risk of developing drug-related side effects when standard doses of these drugs are administered. Deficient N-oxidation of sparteine and 4-hydroxylation of debrisoquine are the same or very similar pharmacogenetic entities whose metabolism is controlled by the same or very similar gene locus, since non-metabolisers of sparteine are poor metabolisers of debrisoquine. In poor and non-metabolisers, impaired metabolism is not restricted to these 2 drugs. Poor metabolisers of debrisoquine exhibited an impaired capacity to effect O-de-ethylation of phenacetin, p-hydroxylation of phenytoin, p-hydroxylation of phenformin, aromatic hydroxylation of guanoxan and benzylic hydroxylation of nortriptyline. The metabolism of antipyrine, tolbutamide and acetanilide, however, was not impaired in the poor and non-metaboliser phenotypes. The poor metaboliser phenotype seems to be at higher risk of developing methaemoglobinaemia following phenacetin administration. Furthermore, impaired phenformin metabolism in the poor and non-metaboliser phenotypes might be one factor predisposing to the development of lactic acidosis.Besides these pharmacogenetic defects, slow metabolism of tolbutamide has been discovered as a new pharmacogenetic entity which might be related to the higher incidence of cardiovascular death occurring during treatment with this hypoglycaemic drug.Although polygenic control of nortriptyline kinetics had been proposed some years ago, the recent finding that non- and poor metaboliser subjects have an impaired capacity to carry out stereospecific E-10-hydroxylation of nortriptyline might suggest monogenic control of this benzylic hydroxylation reaction.Genetically determined deficiency of stereospecific p-hydroxylation of mephenytoin has been discovered recently as a new pharmacogenetic defect leading to mephenytoin intoxication when standard doses of the drug are administered to affected persons.These recent discoveries, certain abnormal drug responses should alert the clinical pharmacologist to investigate the kinetics and metabolism of the drug in more detail, and to suspect the possibility of a genetic polymorphism of drug metabolism.

Carbamazepine metabolism in man. Induction and pharmacogenetic aspects.

SummaryThe metabolism of carbamazepine (CBZ) was studied in 3 groups of subjects: (1) 6 healthy volunteers given a single dose of 200mg carbamazepine; (2) 4 epileptic patients on carbamazepine monotherapy; and (3) 5 patients receiving carbamazepine in combination with other anticonvulsants. Carbamazepine kinetics in the patients were investigated by use of 15N-CBZ. The mean plasma clearances of carbamazepine were 19.8, 54.6 and 113.3 ml/h/kg in groups 1, 2 and 3, respectively. The increased clearance in the patients was mainly due to an induction of the epoxide-diol pathway, as reflected by an increased urinary excretion of the trans-CBZ-diol metabolite. The urinary excretion (as a percentage of the administered dose) of 9-hydroxymethyl-10-carbamoyl-acridan (9-OH-CBZ) was also increased, whereas the excretion of 2-OH-CBZ and 3-OH-CBZ in groups 2 and 3 were decreased in comparison with group 1.As it has been suggested that 9-OH-CBZ is formed from carbamazepine- 10,11-epoxide (CBZ-E) or trans-CBZ-diol, the formation of 9-OH-CBZ was investigated in 3 patients with trigeminal neuralgia treated with carbamazepine or CBZ-E as monotherapy on separate occasions. The urinary excretion of 9-OH-CBZ was 1.9, 3.3 and 4.0% of the trans-CBZ-diol excretion during CBZ-E therapy and 23, 32 and 24%, respectively, during carbamazepine administration. Thus only a minor part of the 9-OH-CBZ excreted in urine during carbamazepine therapy is formed via the epoxide-diol pathway.Data on plasma concentrations of carbamazepine and CBZ-E, and on urinary excretion of trans-CBZ-diol from 4 patients on carbamazepine therapy were used to calculate the plasma clearance of CBZ-E. The hydration of CBZ-E during carbamazepine therapy was found to be induced, but to a lesser extent than the epoxidation of carbamazepine.The interrelationship between carbamazepine-epoxidation and oxidative metabolic reactions of some other drugs was also studied in 8 healthy volunteers. Carbamazepine-epoxidation was not correlated to 4-hydroxylation of debrisoquine, oxidation of sparteine, 3- and 4-hydroxylation and demethylation of antipyrine, demethylation of amitriptyline, or total metabolism of theophylline.

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 < 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.

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)

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.

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, phénobarbital, ethosuximide, or methsuximide further induces carbamazepine metabolism.

Drug Metabolism in Thyroid Disease

SummaryThyroid dysfunction can influence the physiological disposition of drugs. Depending on the pharmacokinetic properties of the individual drug, changes in the rate of metabolism ranging from profound to moderate or negligible have been observed. Since renal function is also influenced by thyroid disease, changes in renal elimination of drugs which are excreted in the urine mainly as unchanged drugs have to be considered as another reason for altered drug disposition in thyroid disease.In patients with thyrotoxicosis, lower, and in patients with myxoedema, higher, digitalis plasma levels have been observed. The altered disposition of cardiac glycosides in thyroid dysfunction can be attributed to changes in renal elimination and metabolism. These findings may be the kinetic correlate for the clinical observation that larger than the usual dose of digitalis is required in thyrotoxic patients and lower in hypothyroid patients.Antipyrine half-lives are very much shortened during hyperthyroidism and prolonged appreciably during hypothyroidism. The alterations in the disposition of these drugs seen during thyroid dysfunction can be ascribed to changes in its rate of metabolism which is controlled by the levels of circulating thyroid hormones. N-demethylation of aminopyrine is depressed both in hyper- and hypothyroid patients as compared with euthyroid subjects. Changes in the half-life of this drug were observed only during hypothyroidism. The physiological disposition of the antithyroid drug propylthiouracil is not changed during thyrotoxicosis. A decrease in plasma half-life of methimazole is however, observed during hyperthyroidism, whereas in hypothyroid patients half-life is increased.The few data available so far do not allow general prediction of how thyroid disease could alter drug metabolism in man.

Influence of the defective metabolism of sparteine on its pharmacokinetics

SummarySparteine is metabolized by N1-oxidation, which in some subjects is defective. The defect has a pronounced effect on the kinetics of the drug. In non-metabolisers 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 β-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).

Superiority of stable isotope techniques in the assessment of the bioavailability of drugs undergoing extensive first pass elimination

SummaryAlthough 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%.