Biomedical subjects

M Eichelbaum

Publications and source records attributed to M Eichelbaum.

At least 73 records · Page 4Linked to original sources

PubMed1998

Gut wall metabolism of verapamil in older people: effects of rifampicin-mediated enzyme induction.

AIMS: To investigate prehepatic metabolism of verapamil and its inducibility by rifampicin in older subjects. METHODS: Eight older subjects (67.1 +/- 1.2 years mean +/- s.d.) received racemic, unlabelled verapamil orally for 16 days (120 mg twice daily). Rifampicin (600 mg daily) was coadministered from day 5 to 16. Using stable isotope technology (i.e. intravenous coadministration of 10 mg deuterated verapamil) during verapamil steady-state without (day 4) and with rifampicin (day 16) bioavailability, prehepatic and hepatic extraction of verapamil were determined. The effects of verapamil on AV-conduction were measured by the maximum PR interval prolongation (%). RESULTS: Bioavailability of the cardiovascularly more active S-verapamil decreased from 14.2 +/- 4.3% on day 4 to 0.6 +/- 0.5% on day 16 (P < 0.001). As a consequence, effects of orally administered verapamil on the AV-conduction were nearly abolished (14.4 +/- 9.4% vs 2.7 +/- 2.6%, P < 0.01). This could be attributed to a considerable increase of prehepatic extraction during treatment with rifampicin (41.7 +/- 22.1% vs 91.6 +/- 6.6%, P < 0.01) and to a minor extent to induction of hepatic metabolism (73.7 +/- 9.4% vs 91.6 +/- 5.3%, P < 0.01). CONCLUSIONS: Prehepatic metabolism of verapamil occurred in the group of older people investigated. Induction of gut wall metabolism most likely was the major reason for the loss of verapamil effect during treatment with rifampicin in this group of older subjects.

Aged↗

PubMed1998

Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population.

The polymorphic cytochrome P450 CYP2D6 catalyses the biotransformation of at least 40 drugs. The CYP2D6 genetic polymorphism is responsible for pronounced interindividual differences in plasma concentrations and, hence, in drug action and side-effects after administration of the same dose. Provided there is a close relationship between CYP2D6 genotypes and catalytic function, genotyping could be used in the clinical setting for individualization of drug dose. In the present study, we evaluated the relationship between the in-vivo enzyme activity and 35 different genotypes in order to determine whether genotyping can be used to predict a person's metabolic capacity for CYP2D6-catalysed drug oxidation using sparteine as a probe drug. One hundred and ninety-five Caucasian individuals were genotyped for seven nonfunctional (CYP2D6 x 3, x 4, x 5, x 6, x 7, x 8, x 16) and eight functional alleles (CYP2D6 x 1, x 2, x 2 x 2, x 2B, x 2B x 2, x 9, x 10, x 17). The metabolic ratio distribution for sparteine showed trimodality, with 15 poor metabolizers, 21 intermediate metabolizers, and 1.59 extensive and ultrarapid metabolizers. All poor metabolizers were unambiguously identified as carriers of two nonfunctional alleles. In contrast, the most frequent functional genotypes extensively overlapped and, with few exceptions, genotype was not a useful predictor of function. Gene dose effects among homozygotes and heterozygotes of the major functional alleles were not significant and could not explain the wide variations. Only a minor fraction of phenotypical ultrarapid metabolizers, arbitrarily defined as individuals with a metabolic ratio < 0.2, could be identified as carriers of three functional gene copies, including duplicated CYP2D6 x 2 x 2 alleles. Similarly, only a minor fraction of the intermediate metabolizers had predictive genotypes involving alleles coding for enzyme with impaired function. Thus, genotyping correctly identifies poor metabolizers, but quantitative prediction of drug metabolism capacity among extensive metabolizers is not possible.

Adolescent↗

PubMed1997

Impact of P450 genetic polymorphism on the first-pass extraction of cardiovascular and neuroactive drugs.

This review highlights the present knowledge on the CYP2D6 (sparteine/debrisoquine) and the CYP2C19 (mephenytoin) polymorphisms. The relevant mutations at genomic level affecting protein expression and function and consequences for first-pass metabolism and effects of cardiovascular and neuroactive drugs are highlighted. In vitro techniques for identification of metabolic steps catalyzed by polymorphic enzymes will be discussed as well as drug-drug interactions related to CYP2D6 and CYP2C19. The importance of the CYP2D6 polymorphism arises from the fact that this enzyme, which is involved in metabolism of more than 50 drugs, is not active in about 8% of a Caucasian population. This group is named poor metabolizers in contrast to the remainder of the population called extensive metabolizers. Depending on the pharmacokinetic and pharmacodynamic properties of the administered drug and its metabolites elevated concentrations of the parent compound can result in an increased risk of toxicity or loss of therapeutic effects in poor metabolizers. On the other hand ultrarapid metabolizers of CYP2D6 might require higher doses than recommended in order to achieve therapeutic drug levels. Moreover, consequences of polymorphic CYP2C19 expression, which is not active in 20% of Orientals and 3% of Caucasians, for drug disposition will be outlined.

Journal Article↗

PubMed1997

High-performance liquid chromatographic determination of acrolein as a marker for cyclophosphamide bioactivation in human liver microsomes.

A high-performance liquid chromatographic method for the quantification of acrolein following incubation of cyclophosphamide (CP) with human liver microsomes was developed. Based on the formation of the fluorescent derivative 7-hydroxyquinoline by condensation of acrolein with 3-aminophenol quantitation was performed without prior extraction or other sample cleanup procedures. The method showed sufficient sensitivity with a limit of detection of 5 ng/ml and a limit of quantification of 10 ng/ml. The suitability of the method is shown for enzyme kinetic studies.

Acrolein↗

PubMed1997

Functional properties of CYP2D6 1 (wild-type) and CYP2D6 7 (His324Pro) expressed by recombinant baculovirus in insect cells.

The debrisoquine/sparteine or CYP2D6 genetic polymorphism of drug oxidation is a common cause for interindividual variability in drug response. We recently identified a mutant allele, designated CYP2D6-E or CYP2D6*7, which is associated with the poor metabolizer phenotype and occurs in Caucasian populations with a frequency of about 1%. In contrast to other loss-of-function alleles, a full length protein with a single amino acid substitution. His324Pro, is encoded by the CYP2D6*7 allele. To functionally analyze this mutant protein form of CYP2D6, recombinant baculoviruses were constructed to express the CYP2D6 cDNA. Up to 0.33 nmol of spectrally detected P450/mg of cell protein were produced in Spodoptera frugiperda cells, whereas Trichoplusia ni 5B1-4 cells reproducibly produced 0.8 nmol/mg (4% of total cell protein). Insect cell membranes were functionally characterized with cumene hydroperoxide or after reconstitution with purified rat NADPH:cytochrome P450 reductase. Km values for the substrates bufuralol and sparteine and other enzymatic properties were almost identical to those of human liver microsomes. The H324P mutation was introduced into the cDNA by site-directed mutagenesis and recombinant baculovirus was obtained. Expression under a variety of conditions demonstrated that mutant protein amounts comparable to the wild-type enzyme were produced. However, no spectrally detectable P450 was formed and no catalytic activity was detected. Furthermore, in contrast to the wild-type protein the mutant protein was almost exclusively located in a detergent-insoluble insect cell fraction. These results demonstrate that the H324P mutation is responsible for the in vivo poor metabolizer phenotype associated with the CYP2D6*7 allele by preventing normal protein folding and heme incorporation.

Animals↗

PubMed1997

Effect of codeine on gastrointestinal motility in relation to CYP2D6 phenotype.

BACKGROUND: Codeine is widely used as an analgesic and antitussive drug. The analgesic effect of codeine is mediated by its metabolite morphine, which is formed by the polymorphically expressed enzyme CYP2D6; therefore poor metabolizers have no analgesia after administration of codeine. Like other opiates, codeine causes a delay of gastric emptying and spastic constipation. It is not yet known whether the effect on gastrointestinal motility is mediated by codeine or its metabolite morphine. METHODS: To test the hypothesis that the metabolite morphine is responsible for the effects of codeine on gastrointestinal motility, a randomized, double-blind, two-way crossover study was performed. The orocecal transit time was studied in five extensive and five poor metabolizers of sparteine with the sulfasalazine-sulfapyridine method, assuming that no effects are observed in poor metabolizers because negligible amounts of morphine are formed. RESULTS: No differences of orocecal transit times were observed between extensive metabolizers and poor metabolizers after oral placebo administration. However, after oral codeine administration orocecal transit time was significantly prolonged in extensive metabolizer but not poor metabolizer subjects. All pharmacokinetic parameters of codeine showed no differences between extensive metabolizers and poor metabolizers. The pharmacokinetic parameters (mean +/- SD) of the metabolite morphine were significantly different between extensive metabolizer and poor metabolizer subjects (peak serum concentration, 13.9 +/- 10.5 versus 0.68 +/- 0.15 pmol/ml; area under the serum concentration-time curve, 27.8 +/- 16.0 versus 1.9 +/- 0.7 hr.pmol/ml; total amount of morphine excreted in urine, 0.160 +/- 0.036 versus 0.015 +/- 0.007 mumol). CONCLUSIONS: Because the orocecal transit time prolongation after codeine administration was observed only in extensive metabolizers, the effect of codeine on gastrointestinal motility, like the analgesia, is mediated by its metabolite morphine.

Analgesics, Opioid↗

PubMed1997

Loss of analgesic effect of morphine due to coadministration of rifampin.

Methadone withdrawal symptoms have been reported in drug addicts treated with the tuberculostatic rifampin. Whereas this interaction can be explained by induction of phase I drug metabolism (CYP3A4), knowledge about induction of phase II metabolism (e.g., UDP-glucuronosyltransferases = UGTs) and its influence on drug effects in man, however, is very limited. The potent analgesic morphine is metabolized by more than one UGT to the active metabolite morphine-6-glucuronide and to morphine-3-glucuronide, which is devoid of analgesic activity. Thus, differential induction of UGTs involved in metabolism of morphine might lead to decreased or increased analgesic effects, depending on which UGT is preferentially induced. We therefore investigated the influence of the potent enzyme inducer rifampin on analgesic effects and pharmacokinetics of morphine, which is primarily eliminated by phase II metabolism. Ten healthy male volunteers participated in this double-blind, placebo-controlled study with double crossover design. Morphine (10 mg p.o.) and placebo were administered on two separate occasions before and near the end of 13 days of treatment with rifampin (600 mg/day). Blood samples were collected for 31 h. Morphine effects on pain sensation were determined using the cold pressor test. When morphine was given alone, the opioid elicited a significant increase in pain threshold and pain tolerance in comparison to placebo (P < or = 0.05). However, following administration of rifampin no analgesic effect of morphine was observed. In agreement, the area under the serum concentration-time curve (AUC) of morphine and the maximum serum concentration of morphine were considerably reduced during coadministration of rifampin (-27.7 +/- 19.3% and -40.7 +/- 27.1%; P < or = 0.01). Moreover, during treatment with rifampin a proportional reduction of AUCs of morphine-3-glucuronide (P < or = 0.01), morphine-6-glucuronide (P < or = 0.05) and morphine was observed. Since urinary recoveries of both morphine-3-glucuronide and morphine-6-glucuronide were also reduced during administration of rifampin, there is no evidence for a contribution of UGT induction to the observed interaction. In summary, a major drug interaction was observed between morphine and rifampin, which could not be attributed to induction of UGTs, but resulted in a complete loss of analgesic effects of the opioid.

Adult↗

PubMed1997

Dose escalation of cyclophosphamide in patients with breast cancer: consequences for pharmacokinetics and metabolism.

PURPOSE: The alkylating anticancer agent cyclophosphamide (CP) is a prodrug that undergoes a complex metabolism in humans producing both active and inactive metabolites. In parallel, unchanged CP is excreted via the kidneys. The aim of this study was to investigate the influence of dose escalation on CP pharmacokinetics and relative contribution of activating and inactivating elimination pathways. PATIENTS AND METHODS: Pharmacokinetics of CP were assessed in 12 patients with high-risk primary breast cancer who received an adjuvant chemotherapy regimen that included four courses of conventional-dose CP (500 mg/m2 over 1 hour every 3 weeks) followed by one final course of high-dose CP (100 mg/kg over 1 hour). Plasma concentrations of CP were analyzed by high-performance liquid chromatography (HPLC), 24-hour urinary concentrations of CP, and its inactive metabolites (carboxyphosphamide, dechloroethylcyclophosphamide [dechlorethylCP], ketocyclophosphamide [ketoCP]) were determined by 31-phosphorus-nuclear magnetic resonance (31P-NMR)-spectroscopy. RESULTS: There was no difference in dose-corrected area under the concentration-time curve (AUC) (216 v 223 [mumol.h/[mL.g]), elimination half-life (4.8 v 4.8 hours), systemic clearance (79 v 77 mL/min) and volume of distribution (0.49 v 0.45 L/kg) of CP between conventional- and high-dose therapy, respectively. However, during high-dose chemotherapy, we observed a significant increase in the renal clearance of CP (15 v 23 mL/min; P < .01) and in the formation clearance of carboxyphosphamide (7 v 12 mL/min; P < .05) and dechloroethylCP (3.2 v 4.2 mL/min; P < .05), whereas metabolic clearance to ketoCP remained unchanged (1.3 v 1.2 mL/min). Consequently, metabolic clearance to the remaining (reactive) metabolites decreased from 52 to 38 mL/min (P < .001). The relative contribution of the different elimination pathways to overall clearance of CP demonstrated wide interindividual variability. CONCLUSION: Overall pharmacokinetics of CP are apparently not affected during eightfold dose escalation. However, there is a shift in the relative contribution of different clearances to systemic CP clearance in favor of inactivating elimination pathways, thereby indicating saturation of bioactivating enzymes during dose escalation. Besides individual enzyme capacity, hydration and concomitant medication with dexamethasone modulated CP disposition.

Adult↗

PubMed1997

Pharmacokinetics and pharmacodynamics of the enantiomers of gallopamil.

The pharmacokinetics and pharmacodynamics of the enantiomers of the calcium antagonist gallopamil have been investigated in six healthy volunteers. Each subject was studied on five occasions after receiving, in randomized order: placebo, 25 mg of (R)-gallopamil, 25 mg of (S)-gallopamil, 50 mg of pseudoracemic [25 mg of deuterated (S)-gallopamil and 25 mg of (R)-gallopamil] and 100 mg of (R)-gallopamil HCl orally. After separate administration, the apparent oral clearances of both enantiomers were similar [(R), 15.1 +/- 9.9 liters/min; (S), 11.0 +/- 6.0 liters/min], indicating that gallopamil first-pass metabolism is not stereoselective. After coadministration, the apparent oral clearance of each enantiomers decreased [(R), 5.9 +/- 2.8 liters/min; (S), 5.8 +/- 2.66 liters/min], suggesting that a partial saturation of first-pass metabolism occurs because the dose was twice as high than for the single enantiomers. Serum protein binding and renal elimination of gallopamil are stereoselective, favoring (S)-gallopamil. Analysis of urine samples revealed a marked degree of stereoselectivity in the formation of O- and N-dealkyl metabolites. Because these showed opposite stereoselectivity, canceling out each other, the net result was no or only marginal stereoselectivity. Twenty-five milligrams of (S)-gallopamil prolonged the PR interval in all subjects; however, a greater effect was elicited by 50 mg of (RS)-gallopamil. (R)-Gallopamil (100 mg) did not significantly alter the PR interval, although higher concentrations were attained than after the pseudoracemate. Based on a consideration of (S)-gallopamil serum concentrations, a comparable relationship between (S)-gallopamil level and effect occurred after (S)- and (RS)-gallopamil, indicating that the pharmacological effect produced by the racemate could be totally accounted for by the higher concentrations of (S)-gallopamil attained.

Adult↗

PubMed1996

Differential induction of prehepatic and hepatic metabolism of verapamil by rifampin.

Cytochrome P450 (CYP) enzymes, which metabolize numerous drugs, are expressed both in liver and in extrahepatic tissues. CYP3A4 for example is present and inducible by rifampin in epithelial cells of the gastrointestinal tract. It has been shown that such prehepatic metabolism contributes substantially to total clearance of CYP3A4 substrates (e.g., cyclosporine) before and even more pronounced during enzyme induction. We examined the effect of enzyme induction on prehepatic and hepatic metabolism of the model compound R/S-verapamil after simultaneous oral and intravenous administration using a stable isotope technology. This approach allows us to exclude intraindividual day-to-day variability and is therefore suitable to quantitatively assess prehepatic extraction of high-clearance drugs. Moreover, because verapamil is administered as a race-mate with the S-enantiomer being preferentially metabolized, we investigated the influence of induction on stereoselectivity of prehepatic and hepatic metabolism. Eight male volunteers received 120 mg of racemic verapamil bid for 24 days. Rifampin (600 mg daily) was given from day 5 to day 16. Systemic clearance and bioavailability of the verapamil enantiomers were determined by coadministering deuterated verapamil intravenously on day 4, on day 16, and on day 24. Effects of verapamil on atrioventricular conduction after oral and intravenous (iv) administration were assessed by measuring the maximum PR-interval prolongation Rifampin increased the systemic clearance of the active S-verapamil 1.3-fold (P < .001). In contrast, rifampin increased the apparent oral clearance of S-verapamil 32-fold (P < .001) and decreased its bioavailability 25-fold (P < .001), with partial recovery after rifampin withdrawal (P < .01). With rifampin, the effect of oral verapamil on atrioventricular conduction was nearly abolished (P < .01), whereas no significant changes were observed after intravenous administration. Induction caused a considerable reduction of stereoselectivity after both intravenous and oral administration (P < .001). Rifampin altered the pharmacokinetics and the pharmacological effects of verapamil to a much greater extent after oral administration compared with intravenous administration. These data clearly indicate that prehepatic metabolism of verapamil (presumably in the gut wall) is preferentially induced compared with hepatic metabolism and that stereoselectivity of verapamil metabolism is affected by induction.

Administration, Oral↗

PubMed1996

Identification of N2 as a metabolite of acetylhydrazine in the rat.

In the pathogenesis of isoniazid-induced hepatic injury, cytochrome P450-dependent metabolic activation of the metabolite, acetylhydrazine (AcHz), is the crucial step. Exhalation of [14C]-carbon dioxide has previously been used to quantify indirectly this pathway. In contrast, according to the current concept of AcHz bioactivation, molecular nitrogen is produced directly, but has not yet been identified. Here, we measured [15N]-nitrogen and 14CO2 exhalation, after the administration of [15N2]-[14C]-AcHz, in rats. Laser magnetic resonance (LMR) spectroscopy, a new sensitive and specific technique for the measurement of 15N and 14N in gas samples, was used. To demonstrate the involvement of cytochrome P450, rats were treated with phenobarbital (PB) or PB+cobalt(II) chloride (CoCl2) (n = 3 in each group). Time-dependent 15N2 exhalation differed significantly between treatment groups (p < 0.001). At 240 min, cumulative exhalation of 15N was 1.92 +/- 0.43% (mean +/- SE) of the dose in the control group, 2.53 +/- 0.23% in the PB group, and 1.00 +/- 0.15% in the PB+CoCl2 group (p < 0.05 compared to controls, p < 0.01 compared to PB). Cumulative exhalation of 14CO2 in 24 h ranged from 15.1 to 21.9%, with no significant difference between treatment groups. In conclusion, N2 is a metabolite of AcHz. N2 formation reflects the cytochrome P450-mediated activation of AcHz and can be used as an index of this pathway. Generally, LMR spectroscopy is valuable for monitoring any N2-liberating process in vivo.

Animals↗

PubMed1996

Characterization of the cytochrome P450 involved in side-chain oxidation of cyclophosphamide in humans.

OBJECTIVE: Cyclophosphamide (CP) is an antineoplastic prodrug which requires bioactivation (4-hydroxylation) by the cytochrome P450 (CYP) enzymes in human liver. In parallel, P450-mediated side-chain oxidation (N-dealkylation) leads to the formation of the non-alkylating dechloroethylcyclophosphamide (DCI-CP) and chloroacetaldehyde, the latter being a potential neurotoxic agent. The enzyme responsible for side-chain oxidation has not been identified yet. We therefore used an in vitro approach to characterize the enzyme involved in N-dealkylation of CP. METHODS: CP was incubated with the microsomal fraction of human liver in the presence of specific inhibitors for some P450 enzymes and in the presence of stable expressed P450 enzymes. Dechloroethylcyclophosphamide was analysed using gas chromatography and nitrogen-phosphorus detection. RESULTS: Formation of DCl-CP increased linearly with substrate concentration over the entire concentration range (20 mumol.l-1 to 36 mmol.l-1). Saturation of the enzyme was not observed. Incubation with stable expressed P450 enzymes and inhibition experiments indicated that CYP3A4 was the major enzyme involved in side-chain oxidation of CP. CONCLUSION: Our in vitro data indicate that side-chain oxidation of CP occurs in dose-dependent fashion in men with no saturation of this pathway even following dose escalation. Thus enhanced neurotoxicity following CP administration may result in the setting of high-dose chemotherapy. Moreover, we conclude that CP has the potential to interact with other CYP 3A4 substrates.

Antineoplastic Agents, Alkylating↗

PubMed1996

Antipyrine as a probe for human oxidative drug metabolism: identification of the cytochrome P450 enzymes catalyzing 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine formation.

BACKGROUND AND OBJECTIVE: Antipyrine has been widely used as a probe drug for human oxidative drug metabolism. To evaluate the role of antipyrine as a model drug, we have identified the cytochrome P450 enzymes involved in 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine formation. METHODS: We used the following methods for this study: (1) determination of enzyme kinetics for antipyrine metabolite formation in human liver microsomes, (2) inhibition studies with antibodies and inhibitors, and (3) formation of metabolites by stable expressed human P450 enzymes. RESULTS: Antipyrine biotransformation could be described by Michaelis-Menten kinetics: norantipyrine: maximum rate of metabolite formation (Vmax), 0.91 +/- 0.04 nmol . mg-1 . min-1; Michaelis-Menten constant (Km), 19.0 +/- 0.8 mmol/L; 4-hydroxyantipyrine: Vmax, 1.54 +/- 0.08 nmol . mg-1 . min-1;Km,39.6 +/- 2.5 mmol/L. Antibodies against CYP3A4 inhibited the formation of 4-hydroxyantipyrine by 25% to 65%. LKM-2 antibodies (anti-CYP2C) caused a 75% to 100% inhibition of norantipyrine and a 58% to 80% inhibition of 3-hydroxymethylantipyrine formation. Sulfaphenazole inhibited the formation of 3-hydroxymethylantipyrine and norantipyrine by about 50%. Furafylline and fluvoxamine inhibited norantipyrine, 4-hydroxyantipyrine, and 3-hydroxymethylantipyrine formation by about 30%, 30%, and 50%, respectively. Ketoconazole reduced formation of norantipyrine, 3-hydroxymethylantipyrine, and 4-hydroxyantipyrine by up to 80%. Formation in stable expressed enzymes indicated involvement of CYP1A2, CYP2B6, CYP2C, and CYP3A4 in metabolite formation. CONCLUSION: Antipyrine metabolites are formed by at least six hepatic cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, and CYP3A4). 4-Hydroxylation is mainly catalyzed by CYP3A4 and, to a lesser extent, by CYP1A2. The CYP2C subfamily contains the predominant enzymes for norantipyrine formation, and CYP1A2 is also involved. Formation of 3-hydroxymethylantipyrine is mediated by CYP1A2 and CYP2C9. Because several cytochrome P450 enzymes are involved in the formation of each metabolite, antipyrine is not well suited as a probe for distinct human cytochrome P450 enzymes.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1996

Assessment of individual CYP2D6 activity in extensive metabolizers with renal failure: comparison of sparteine and dextromethorphan.

OBJECTIVES: To examine whether the variability of CYP2D6 activity in patients with chronic renal failure can be assessed, particularly among subjects with the extensive metabolizer phenotype, by use of standard in vivo indexes of CYP2D6 activity derived from oral administration of dextromethorphan and sparteine. METHODS: A single 100 mg oral dose of sparteine and a single 40 mg oral dose of dextromethorphan were administered on two occasions to 12 patients with chronic renal failure (creatinine clearance ranging from 20 to 70 ml/min) and 12 age- and sex-matched healthy subjects. Sparteine clearances, sparteine metabolic ratio, and urinary recovery of dextrorphan were calculated. Patients and healthy control subjects were not selected on the basis of their CYP2D6 phenotypes. RESULTS: Chronic renal failure was associated with a decrease in sparteine partial metabolic clearance to dehydrosparteine (median of 322 ml/min and range of 62 to 670 ml/min in patients with renal failure versus median of 635 ml/min and range of 77 to 1276 ml/min in normal subjects; p < 0.02). Sparteine apparent oral clearance (p < 0.03) and renal clearance (p < 0.001) decreased in patients with renal failure. However, sparteine metabolic ratio was not significantly altered in patients with renal failure and showed that all patients were extensive metabolizers of sparteine. Although fractional urinary excretion of dextrorphan decreased in patients with renal failure (median, 24.4%; range, 9.7% to 55.9%) compared with control (median, 47.5%; range, 24.1% to 72.1%) (p = 0.02), it also showed that all subjects were extensive metabolizers of dextromethorphan. The amount of dextromethorphan excreted in urine correlated with creatinine clearance independently from CYP2D6 activity measured as sparteine partial metabolic clearance. However, it did not correlate with sparteine metabolic ratio or with fractional urinary excretion of dehydrosparteine. CONCLUSION: Assessment of CYP2D6 activity by use of dextromethorphan and sparteine is possible in extensive metabolizer patients with chronic renal failure. However, in these subjects, dextromethorphan and sparteine do not reflect CYP2D6 activity in the same way.

Administration, Oral↗

PubMed1996

Stereoselectivity in drug metabolism and action: effects of enzyme inhibition and induction.

Many synthetic drugs that contain a chiral center are marketed as racemates. Taking into account the composite nature of chiral rugs has improved our understanding of the dose/effect relationship of these compounds. It is widely accepted that drug metabolism is often responsible for stereoselective disposition and hence factors modulating the activity of drug-metabolizing enzymes can modify this effect. The present article highlights the influence of some of these factors (induction and inhibition of drug-metabolizing enzymes) on stereoselective drug disposition. The latter topic includes an enantiomer/enantiomer interaction that alters drug disposition and drug action.

Drug Interactions↗

PubMed1996

Nomenclature for human CYP2D6 alleles.

To standardize CYP2D6 allele nomenclature, and to conform with international human gene nomenclature guidelines, an alternative to the current arbitrary system is described. Based on recommendations for human genome nomenclature, we propose that alleles be designated by CYP2D6 followed by an asterisk and a combination of roman letters and arabic numerals distinct for each allele with the number specifying the key mutation and, where appropriate, a letter specifying additional mutations. Criteria for classification as a separate allele and protein nomenclature are also presented.

Alleles↗

PubMed1996

Rapid detection of CYP2D6 null alleles by long distance- and multiplex-polymerase chain reaction.

The CYP2D6 gene on human chromosome 22 encodes a cytochrome P450 responsible for oxidative metabolism of over 30 clinically used drugs. The CYP2D6 gene is highly polymorphic with more than 20 alleles described to date. Some of these harbour loss-of-function mutations which lead to the poor metabolizer phenotype in 5-10% of Caucasians. These individuals are at increased risk of suffering from adverse side effects or to experience therapeutic failure following drug treatment. Phenotype determination requires ingestion of a probe drug and has other inherent problems. Due to the increasing number of alleles known, comprehensive CYP2D6 genotyping using the conventional assays has become cumbersome and time consuming. We have therefore developed a streamlined and more rapid CYP2D6 genotyping procedure. Use of long distance PCR allowed the amplification of a 4666 bp fragment which contains the entire CYP2D6 gene. The 4.7 kb fragment serves as a template for a multiplex allele-specific PCR assay to simultaneously identify the five PM-associated alleles, CYP2D6*3 (A), *4 (B), *6 (T), *7 (E), and *8 (G). Together with the CYP2D6 deletion allele CYP2D6*5 (D), which can be detected in a separate PCR assay, these alleles are responsible for the PM phenotype in approximately 99% of Caucasian individuals. We tested the reliability of the procedure by analysing DNA from more than 80 individuals with known CYP2D6 genotypes. Twelve different genotypes were present among these samples and all of them were correctly identified.

Alleles↗

PubMed1996

Antidepressants and drug-metabolizing enzymes--expert group report.

Antidepressant drugs are extensively metabolized. Consequently, the biotransformation pattern of antidepressants has an important influence on their clinical properties, i.e., pharmacokinetics, toxicity, drug-drug interactions, side-effect profile and last but not least therapeutic efficacy. It was against this background that a multidisciplinary group of experts discussed the clinical relevance of the rapidly increasing body of knowledge of antidepressant-metabolizing enzymes. The variability of the response of a given individual to an antidepressant is determined genetically and by the environment. Genetic polymorphism of drug-metabolizing enzymes and inhibition by other substrates may affect the enzymatic biotransformation of antidepressants. In vitro assay techniques allow an estimation of the potential variability in clinical response to antidepressants and a reasonable prediction of the drug-drug interaction patterns. The results of in vitro tests should therefore be considered early in the development of an antidepressant as a background for designing clinical studies (treatment schedules and dosing). Physicians should have an understanding of the relevance of genetic polymorphism for clinical practice. Education is needed in order to fill the existing gaps in knowledge about antidepressant-enzyme interactions and their application in daily treatment practice. The information on potential drug interactions determined by genetic polymorphism and based on studies with enzymes should be increasingly contained in drug compendia.

Antidepressive Agents↗