Biomedical subjects
Publications and source records attributed to M Eichelbaum.
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.
The potential to inhibit drug metabolism of the new antifungal agent terbinafine has been studied using antipyrine (single oral dose of 10 mg/kg) as a probe drug. In a cross-over study in 8 healthy volunteers, antipyrine was administered prior to, during and after 8 days of oral terbinafine 125 mg b.d. Antipyrine, its major metabolites 4-hydroxyantipyrine (4-OH-AP), 3-hydroxymethylantipyrine (3-OH-CH3-AP) and norantipyrine (Nor-AP) were analyzed by specific HPLC assays in multiple plasma and urine samples. During all three parts of the study, the pharmacokinetics of antipyrine viz. t1/2 (11.7 h), total plasma (38.5 ml.h-1.kg-1) and renal clearance (1.6 ml.h-1.kg-1), and its clearance rates to metabolites (CLM), eg. CLM for 4-OH-AP (12.3 ml.h-1.kg-1), CLM for 3-OH-CH3-AP (4.2 ml.h-1.kg-1) and CLM for Nor-AP (6.7 ml.h-1.kg-1) did not differ from the control values. Thus, all the cytochrome P-450-dependent isozymes involved in the metabolism of antipyrine and many other drugs should not be affected by therapeutic doses of terbinafine.
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.
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 (11.8 versus 6.8 hours), and the amount excreted in the urine was higher (26.7 +/- 7.2 versus 15.4 +/- 1.3 mg) in PMs compared with EMs (p less than 0.05). Oral clearance of flecainide was reduced (p less than 0.019) in PMs (600 +/- 139 versus 1041 +/- 307 ml/min in EMs). The renal clearance was similar (p greater than 0.05) in PMs (308 +/- 70 ml/min) and EMs (315 +/- 69 ml/min) and, consequently, PMs had a lower (p less than 0.008) metabolic clearance of flecainide (292 +/- 136 versus 726 +/- 240 ml/min in EMs). Under conditions of uncontrolled urinary flow and pH, renal excretion of flecainide will be reduced and the difference in disposition will be greater. In PMs with renal impairment, accumulation of flecainide to very high serum concentrations may be anticipated, and this may result in proarrhythmic effects.
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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. In the EM subjects there were no significant differences in the oral clearance, half-life or urinary excretion of (+)-S- and (-)-R-flecainide. 3. In the PM subjects differences in the pharmacokinetics of S- and R-flecainide were observed. The oral clearance of R-flecainide (467 +/- 109 ml min-1) was less (P less than 0.03) than that of the S-enantiomer (620 +/- 172 ml min-1). The half-life of R-flecainide (12.9 h) was longer (P less than 0.03) than that of S-flecainide (9.8 h). The renal clearance of the two enantiomers was, however, comparable and similar to that observed in the EM subjects. The urinary recovery of R-flecainide (15.6 +/- 3.7 mg) was greater (P less than 0.03) than that of the S-enantiomer (12.0 +/- 3.7 mg). The enantioselective disposition observed in PMs is therefore due to greater impairment in the metabolism of R- than S-flecainide. 4. The urinary recoveries of two major metabolites of flecainide, meta-O-dealkylated flecainide (MODF) and the meta-O-dealkylated lactam of flecainide (MODLF) were lower (P less than 0.05) in PMs, 12.0% +/- 3.1% and 8.2% +/- 3.2% of the dose administered, respectively, than in EMs of 17.7% +/- 3.3% and 16.5% +/- 3.3%, respectively. 5. One PM subject had a greatly diminished flecainide metabolic capacity and a rare genotype, as assigned by Xbal RFLP analysis.
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)
Despite its almost complete absorption following oral administration, gallopamil has an absolute bioavailability of only 15% due to an extensive hepatic first-pass metabolism. During multiple oral dosing bioavailability increases to approximately 25% indicating a partial saturation of first-pass metabolism. Since the half-life time of gallopamil is on average 3-6 h a minimum of three times daily dosing of the instant-release 50 mg tablet is required in order to maintain therapeutic plasma concentrations. The sustained-release 100 mg tablet which recently became available has a relative bioavailability comparable to the instant release preparation. Due to the delayed drug liberation therapeutic plasma concentrations are maintained for 24 h following once or twice daily administration of this drug preparation.
The binding of the (+)- and (-)-enantiomers of verapamil (V) to purified albumin (40 g/L), alpha 1-acid glycoprotein (0.55 g/L) and fresh serum has been studied over a wide range of verapamil concentrations (0.055 to 22 microM). The free fraction of the pharmacologically more potent (-)-V was always greater than that of (+)-V. Similar free fractions were observed in solutions of alpha 1-acid glycoprotein ((+)-V 0.079 +/- 0.016; (-)-V 0.142 +/- 0.020) and fresh serum ((+)-V 0.096 +/- 0.009; (-)-V 0.136 +/- 0.006), however the free fraction was higher in a solution of albumin ((+)-V 0.400 +/- 0.030; (-)-V 0.572 +/- 0.029). Saturation of verapamil binding sites was observed for alpha 1-acid glycoprotein only. Enantioselective verapamil serum binding was also noted in samples collected from five healthy volunteers following oral and intravenous verapamil administration. The free fraction of the individual isomers in vitro when added to predose serum as the pseudoracemic drug ((+)-V 0.06 +/- 0.01, (-)-V 0.12 +/- 0.02) was similar to that observed for the enantiomers when studied separately in vitro, indicating that the binding of each enantiomer is independent of the other optical isomer. The free fraction ex vivo after intravenous therapy ((+)-V 0.06 +/- 0.01, (-)-V 0.12 +/- 0.02) was similar to that observed in vitro in that subjects pre-dose serum. The free fraction of both enantiomers, however, was higher after oral drug therapy ((+)-V 0.13 +/- 0.02, (-)-V 0.23 +/- 0.03). The lower binding noted may be a result of competition for serum binding sites by verapamil metabolites, which attain higher concentrations following oral dosing.
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A stable isotope assay for the quantification of debrisoquine (1) and its major urinary metabolite 4-hydroxydebrisoquine (2) is described. The method consists of extractive derivatization of 1 and 2 by use of 1,3-diketones, chiral derivatization of the 4-hydroxy group of 2, and gas chromatography/negative ion chemical ionization mass spectrometry in the presence of deuterated analogues of 1 and 2. In comparison with synthetic R-(-)-2 and S-(+)-2 it is shown that in vivo benzylic 4-hydroxylation of 1 is highly stereoselective, leading predominantly to S-(+)-4-hydroxydebrisoquine (enantiomeric excess greater than or equal to 90%).
The examples discussed demonstrate the importance of stereoselective drug metabolism and raise the question of whether the therapeutic use of racemic drugs is still justified. There is no straightforward answer to this question. If only quantitative differences in therapeutic activity exist and the less active enantiomer is not predominantly responsible for side effects, the therapeutic benefit gained by using the more active enantiomer is only marginal and does not justify the substantial increase in costs involved in manufacturing such a drug preparation. However, if stereoselectivity in therapeutic activity is pronounced and adverse drug reactions are caused mainly by the less active isomer then an isomeric pure drug preparation should be used.
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Nitrendipine [3-ethyl-5-methyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate] is a calcium antagonist with a dihydropyridine structure that has a great structural resemblance to nifedipine. Instead of a methyl group in position 3, it has an ethyl group and the NO2 group is in the meta instead of in the ortho position. These minor structural differences have a pronounced impact with respect to both the pharmacokinetics and pharmacodynamics of nitrendipine as compared to nifedipine. Based on equimolar plasma concentrations, nitrendipine is on average three times more potent than nifedipine with regard to the reduction of peripheral vascular resistance, arterial blood pressure, and increased leg blood flow. The terminal half-life is on average 8 h, and thus substantially longer than the terminal half-life of 2-3 h for nifedipine. Despite its almost complete absorption, bioavailability is on average 15-25% and shows great interindividual variability ranging from 7 to 40%. The systemic plasma clearance of the drug is on average 18 ml/min/kg and thus approaches the liver blood flow. In patients with liver cirrhosis, the half-life is prolonged to 19.6 h, the total plasma clearance is decreased by 50%, and the bioavailability is more than doubled to 54%. No data are available if liver disease alters the pharmacodynamic response of the drug. Kidney disease has some effect on the disposition of the drug. Systemic clearance is not changed but the terminal elimination half-life is slightly prolonged to 10.5 h. This increase in half-life is due to an increased volume of distribution. Bioavailability, which is 21.2%, is not grossly altered in renal failure.
The electrophysiologic effects of dextro (d)- and levo (l)-verapamil on sinoatrial (SA) and atrioventricular (AV) node function were studied in ten patients undergoing electrophysiologic evaluation of their supraventricular tachyarrhythmias. Both isomers elicited a significant prolongation of sinus node recovery time (SNRT) and AH interval. No difference between d- and l-verapamil regarding the magnitude of the effects were observed. However, 50 mg d-verapamil was required to elicit the same electrophysiologic effects as 5 mg l-verapamil. The d- and l-verapamil plasma concentrations associated with the maximum effect on AH interval and SNRT showed a more than 20-fold difference (d: 380 ng/ml; l: 19 ng/ml). These data demonstrate that both verapamil isomers possess qualitatively similar slow channel blocking effects on the SA and AV node in humans, but the l isomer is 20 times more potent than the d isomer.
Debrisoquine (DQ) has no chiral centre, but hydroxylation in position 4 leads to formation of an asymmetric carbon centre with two possible enantiomers, their absolute configuration being R(-) and S(+)-4-hydroxydebrisoquine (4-OHDQ). Since the absolute stereochemistry of the 4-hydroxylation of DQ in man is unknown, the enantioselectivity of this process was studied in panels of extensive (EM) and poor metabolizers (PM) of DQ. In EM subjects 4-hydroxylation of DQ leads almost exclusively to the formation of S(+)-4-OHDQ. In contrast, PM subjects were not only characterized by a decreased total 4-OHDQ formation but also a marked loss of enantioselectivity in product formation. Between 5 to 36% of total 4-OHDQ was excreted as R(-)-4-OHDQ.
The benzodiazepine midazolam is rapidly eliminated by oxidative metabolism. In young healthy volunteers elimination half-life (t1/2) is about 2.4 hours. A recent study showed a prolonged t1/2 from 8 to 22 hours in 6.5% of surgical patients, and a genetic polymorphism of midazolam's metabolism has been suggested. Therefore, we measured in 168 surgical patients the elimination of midazolam and its major hydroxylated metabolite (alpha-OH-midazolam) in blood and urine. Co-medication, disease status, smoking habits and alcohol intake were recorded; normal liver and kidney functions were assessed by routine laboratory tests. Midazolam was administered intravenously (0.1 to 0.2 mg/kg) for the induction of anaesthesia. Blood was drawn 1.5, 3, 4.5 and 6 hours after application and urine was collected for 6 hours. Plasma protein binding of midazolam was determined by equilibrium dialysis. Midazolam and alpha-OH-midazolam were measured in plasma by specific gas-liquid chromatography and in urine by high performance liquid chromatography. Data for the dose-corrected area under plasma-level curve of midazolam (AUC-midazolam/dose: 1.23 +/- 961 x 10(5) h/ml; mean +/- SD) and for the metabolic plasma ratio (AUC of alpha-OH-midazolam/AUC-midazolam: 0.52 +/- 0.28) demonstrated a log-normal distribution. Likewise, the percentage of the unbound fraction of midazolam in plasma (5.0 +/- 2.4%), urinary excretion of alpha-OH-midazolam (55.9 +/- 22.7% of dose) and the values for t1/2 (2.9 +/- 1.1 hours) did indicate a unimodal distribution. Age, comedication and smoking habits did not affect the disposition of midazolam. However, patients with regular intake of alcohol had a higher (p less than 0.05) metabolic ratio. Only in 3 patients could a prolonged t1/2 of midazolam from 7.5 to 10.2 hours be detected, but plasma levels and urinary excretion of alpha-OH-midazolam in those individuals were found to be normal. Therefore it is very unlikely that the oxidative metabolism of midazolam exhibits a genetic polymorphism.