Concentrations of the enantiomers of fluoxetine and norfluoxetine after multiple doses of fluoxetine in cytochrome P4502D6 poor and extensive metabolizers

Plasma concentrations of the enantiomers of fluoxetine (FLX) and norfluoxetine (NFLX) were measured at days 7, 14, and 23 of oral administration of 20 mg of racemic fluoxetine in 11 patients who were comedicated with risperidone. Eight patients were genotyped as being cytochrome P4502D6 extensive metabolizers (EMs) and three as cytochrome P4502D6 poor metabolizers (PMs). No statistically significant differences were calculated between EMs and PMs in the concentrations of (R)-FLX and (R)-NFLX for all days examined (day 23, mean +/- SD for (R)-FLX and (R)-NFLX in EMs, 16 +/- 5 and 29 +/- 20 ng/mL, respectively; in PMs, 16 +/- 1 and 20 +/- 2 ng/mL, respectively). However, concentrations of (S)-FLX and (S)-NFLX were higher and lower, respectively, in PMs as compared with EMs (day 7, p = 0.037 and p = 0.036; day 14, p = 0.014 and p = 0.014; day 23, p = 0.068 and p = 0.038). On day 23, mean (S)-FLX and (S)-NFLX in EMs were (mean +/- SD) 39 +/- 26 and 63 +/- 26 ng/mL, and in PMs they were 88 +/- 7 and 19 +/- 2 ng/mL. This study confirms the results of the single-dose studies showing that CYP2D6 is involved in the demethylation of FLX to NFLX, with a stereoselectivity toward the (S)-enantiomer. The data also clearly show that the CYP2D6 genotype has an important influence on the concentrations of the (S)- but not of the (R)-enantiomer of FLX and NFLX after multiple doses.     

Variation in the CYP2D6 gene is associated with a lower serum sodium concentration in patients on antidepressants

AIM

To study the effect of the CYP2D6*4 polymorphism on serum sodium concentration in users of antidepressants [selective serotonin reuptake inhibitors and tricyclic antidepressants (TCAs)].

METHODS

In this population-based cohort study, all subjects in the Rotterdam Study were included who used an antidepressant at baseline and from whom a blood sample was available in which CYP2D6 genotype and serum sodium concentration could be determined (n= 76). Multivariate linear regression was used to study the association between CYP2D6*4 and serum sodium concentration.

RESULTS

CYP2D6 poor metabolizers (PMs) (*4/*4) had a significantly lower mean serum sodium concentration in comparison with CYP2D6 extensive metabolizers (EMs) (*1/*1) [difference −3.9 mmol l⁻¹; 95% confidence interval (CI) −0.86, −7.03; P= 0.013]. In CYP2D6*4 heterozygotes (*1/*4) serum sodium concentration was 1.7 mmol l⁻¹ (95% CI −3.48, 0.18) lower compared with CYP2D6 EMs, but this difference was not statistically significant (P= 0.077).

CONCLUSIONS

The serum sodium concentration in PMs was lower in users of an antidepressant, especially in TCA users. Therefore CYP2D6 PMs might be at increased risk of developing symptoms of hyponatraemia.     

Contributions of CYP2D6, CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in healthy volunteers

In-vitro data indicated a contribution of cytochrome P450 enzymes 1A2, 3A4, 2C9, 2C19 and 2D6 to biotransformation of doxepin. We studied the effects of genetic polymorphisms in CYP2D6, CYP2C9 and CYP2C19 on E- and Z-doxepin pharmacokinetics in humans. Doxepin kinetics was studied after a single oral dose of 75 mg in healthy volunteers genotyped as extensive (EM), intermediate (IM) and poor (PM) metabolizers of substrates of CYP2D6 and of CYP2C19 and as slow metabolizers with the CYP2C9 genotype *3/*3. E-, Z-doxepin and -desmethyldoxepin were quantified in plasma by HPLC. Data were analyzed by non-parametric pharmacokinetics and statistics and by population pharmacokinetic modeling considering effects of genotype on clearance and bioavailability. Mean E-doxepin clearance (95% confidence interval) was 406 (390-445), 247 (241-271), and 127 (124-139) l h(-1) in EMs, IMs and PMs of CYP2D6. In addition, EMs had about 2-fold lower bioavailability compared with PMs indicating significant contribution of CYP2D6 to E-doxepin first-pass metabolism. E-doxepin oral clearance was also significantly lower in carriers of CYP2C9*3/*3 (238 l h(-1) ). CYP2C19 was involved in Z-doxepin metabolism with 2.5-fold differences in oral clearances (73 l h(-1) in CYP2C19 PMs compared with 191 l h(-1) in EMs). The area under the curve (0-48 h) of the active metabolite -desmethyldoxepin was dependent on CYP2D6 genotype with a median of 5.28, 1.35, and 1.28 nmol l h(-1) in PMs, IMs, and EMs of CYP2D6. The genetically polymorphic enzymes exhibited highly stereoselective effects on doxepin biotransformation in humans. The CYP2D6 polymorphism had a major impact on E-doxepin pharmacokinetics and CYP2D6 PMs might be at an elevated risk for adverse drug effects when treated with common recommended doses.     

Metabolism, pharmacokinetics, and excretion of a highly selective N-methyl-D-aspartate receptor antagonist, traxoprodil, in human cytochrome P450 2D6 extensive and poor metabolizers.

The excretion, biotransformation, and pharmacokinetics of a selective N-methyl-D-aspartate receptor antagonist, traxoprodil, were investigated in six healthy male volunteers, phenotyped either as CYP2D6 extensive or poor metabolizers of dextromethorphan. Each subject received an i.v. infusion of a single 50-mg (100 microCi) dose of [(14)C]traxoprodil. Approximately 89% of the administered dose was recovered in poor metabolizers (PMs) and 61% in extensive metabolizers (EMs), with the majority of the dose being excreted in the urine (86% in PMs and 52% in EMs). The elimination of traxoprodil was more rapid in EMs than in PMs with terminal elimination half-lives of 2.8 and 26.9 h, respectively, for EMs and PMs. Area under the plasma concentration-time curve from time 0 to T (AUC((0-Tlast))) values for unchanged traxoprodil were 1.2 and 32.7% of the corresponding AUC values for total radioactivity in EMs and PMs, respectively. Traxoprodil was metabolized in both EMs and PMs, with approximately 7 and 50% of the administered radioactivity excreted as unchanged drug in the excreta of EMs and PMs, respectively. Hydroxylation at the 3-position of the hydroxyphenyl ring and methylation of the resulting catechol followed by conjugation were identified as the main metabolic pathways in EMs. In contrast, direct conjugation of traxoprodil with glucuronic or sulfuric acid was the major pathway in PMs. In vitro studies using CYP2D6-selective inhibitor and recombinant enzyme also support that the metabolism of traxoprodil is mainly mediated by CYP2D6. Taken together, these studies suggest that traxoprodil is eliminated mainly by Phase I oxidative metabolism mediated by CYP2D6 isozyme in EMs and by Phase II conjugation and renal clearance of parent in PMs.     

Concordance of P450 2D6 (debrisoquine hydroxylase) phenotype and genotype: inability of dextromethorphan metabolic ratio to discriminate reliably heterozygous and homozygous extensive metabolizers.

Debrisoquine-hydroxylase (P450 2D6) not equal to phenotype was determined in 116 individuals using dextromethorphan as the substrate probe. Polymerase chain reaction and restriction fragment length polymorphism analyses were used to detect inactivating mutations in the CYP2D6 gene and assign genotype in all 116 individuals. Using a urinary metabolic ratio (DM/DT) of > or = 0.3 to define poor metabolizer (PM) phenotypes, 96 subjects were extensive metabolizers (EM) and 20 were PMs. The CYP2D6(B) mutation was the most common mutation, present in 18% of phenotypic EM alleles and 66% of the alleles in PM phenotypes. The CYP2D6(A) mutation (8% of PM alleles) and the CYP2D6 gene deletion (2.6% of PM alleles) were found less frequently. Seven different variants of the CYP2D6 gene were found. In subjects with two mutant alleles, genotype correctly predicted the PM phenotype in 100% (n = 13). Overall, genotype agreed with phenotype assignments in 109 of 116 (94%) subjects. Seven subjects with a wild-type allele at the CYP2D6(A) and CYP2D6(B) loci were phenotypic PMs, representing the only discrepant results. These discrepancies could be due to the imprecision of phenotype assignment or to as yet unknown mutations in CYP2D6. Although the median urinary metabolic ratio was significantly lower in homozygous EMs compared with heterozygous EMs, there was extensive overlap in metabolic ratios in these two groups, indicating that the DM/DT metabolic ratio cannot reliably discriminate homozygous EMs from heterozygous EMs.     

Effect of the CYP2C19 oxidation polymorphism on fluoxetine metabolism in Chinese healthy subjects

AIMS: The study was designed to investigate whether genetically determined CYP2C19 activity affects the metabolism of fluoxetine in healthy subjects. METHODS: A single oral dose of fluoxetine (40 mg) was administrated successively to 14 healthy young men with high (extensive metabolizers, n=8) and low (poor metabolizers, n = 6) CYP2C19 activity. Blood samples were collected for 5-7 half-lives and fluoxetine, and norfluoxetine were determined by reversed-phase high performance liquid chromatography. RESULTS: Poor metabolizers (PMs) showed a mean 46% increase in fluoxetine peak plasma concentrations (Cmax, P < 0.001), 128% increase in area under the concentration vs time curve (AUC(0, infinity), P < 0.001), 113% increase in terminal elimination half-life (t(1/2)) (P < 0.001), and 55% decrease in CLo (P < 0.001) compared with extensive metabolizers (EMs). Mean +/- (s.d) norfluoxetine AUC(0, 192 h) was significantly lower in PMs than that in EMs (1343 +/- 277 vs 2935 +/- 311, P < 0.001). Mean fluoxetine Cmax and AUC(0, infinity) in wild-type homozygotes (CYP2C19*1/CYP2C19*1) were significantly lower than that in PMs (22.4 +/- 3.9 vs 36.7 +/- 8.9, P < 0.001; 732 +/- 42 vs 2152 +/- 492, P < 0.001, respectively). Mean oral clearance in individuals with the wild type homozygous genotype was significantly higher than that in heterozygotes and that in PMs (54.7 +/- 3.4 vs 36.0 +/- 8.7, P < 0.01; 54.7 +/- 3.4 vs 20.6 +/- 6.2, P < 0.001, respectively). Mean norfluoxetine AUC(0, 192 h) in PMs was significantly lower than that in wild type homozygotes (1343 +/- 277 vs 3163 +/- 121, P < 0.05) and that in heterozygotes (1343 +/- 277 vs 2706 +/- 273, P < 0.001), respectively. CONCLUSIONS: The results indicated that CYP2C19 appears to play a major role in the metabolism of fluoxetine, and in particular its N-demethylation among Chinese healthy subjects.     

The major fluvoxamine metabolite in urine is formed by CYP2D6

OBJECTIVE: Previous studies have shown that fluvoxamine is metabolized by CYP1A2 and CYP2D6, but there is no information on the impact the various CYP enzymes have on the different metabolic pathways of fluvoxamine biotransformation. The present study was designed to investigate this issue. METHODS: The major fluvoxamine metabolite, the 5-demethoxylated carboxylic acid metabolite, was analyzed in urine from 50 healthy volunteers after intake of a single oral dose of 50 mg fluvoxamine, and the formation clearance for the metabolite (CLm) was calculated. Of the subjects, 28 were non-smoking CYP2D6 and CYP2C19 extensive metabolizers (EMs), 12 were smokers and were thus considered to have an induced CYP1A2 activity, 5 were CYP2D6 poor metabolizers (PMs), and 5 were CYP2C19 PMs. In 11 of the non-smoking EMs, 200 mg caffeine was given at another occasion in order to calculate oral caffeine clearance as a measure of CYP1A2 activity. In addition, CLm was calculated in ten other subjects given increasing doses of fluvoxamine for 4 weeks. RESULTS: Oral clearance of fluvoxamine was significantly higher in smokers, and significantly lower in CYP2D6 PMs than in non-smoking EMs. CLm was 78% lower in CYP2D6 PMs than in the EMs. Smoking and being a CYP2C19 PM did not influence CLm. There was no significant correlation between oral caffeine clearance and CLm. CLm decreased with increasing fluvoxamine dosage, but the decrease in oral clearance was even higher. CONCLUSION: These results indicate that CYP2D6 catalyzes the major metabolic pathway of fluvoxamine, whereas CYP1A2 seems to catalyze other less important pathways. Both the CYP2D6 and the CYP1A2 pathways seem to be saturated in parallel with increasing fluvoxamine dosage.     

Pharmacokinetics of tramadol enantiomers and their respective phase I metabolites in relation to CYP2D6 phenotype.

OBJECTIVE: Our objective was to evaluate the effect of CYP2D6 phenotype in the enantioselective metabolism of tramadol in Spanish healthy human volunteers. METHODS: A single oral 100mg dose of racemic tramadol was administered to five subjects who were poor metabolizers (PMs) and 19 subjects who were extensive metabolizers (EMs), whose phenotypes were determined by the use of the racemic tramadol metabolic rate. The pharmacokinetic parameters were estimated from plasma concentrations of the enantiomers of tramadol and their main phase I metabolites, O-desmethyltramadol (M1) and N-desmethyltramadol (M2). Epinephrine plasma concentrations were also determinated. RESULTS: The plasma concentrations of both tramadol enantiomers were consistently higher in PMs than in EMs of CYP2D6, with 1.98- and 1.74-fold differences in the mean area under the plasma concentration-time curves (AUC), respectively. The values for oral clearance of (+)- and (--)-tramadol were 1.91- and 1.71-fold greater in PMs, which were related to differences in both O-desmethylation and N-desmethylation in the two CYP2D6 metabolizer phenotypes. The mean AUC values of (+)-M1 and (--)-M1 were 4.33- and 0.89-fold greater in EMs, and it was related to similar differences in the formation rate constant. On the other hand, the differences were 7.40- and 8.69-fold greater in PMs for M2 enantiomers due to the involvement of CYP2D6 in their subsequent biotransformation. The time course of epinephrine systemic concentrations was completely different between both groups of metabolizers. In EMs plasma concentrations of epinephrine increased after tramadol administration whereas in PMs no effect was observed. CONCLUSIONS: The polymorphic CYP2D6 appears to be a major enzyme involved in the metabolism of tramadol enantiomers. The N-desmethylation pathway was indirectly affected by CYP2D6 phenotypic differences. Epinephrine showed a good correlation with the pharmacokinetics of the opioid component of tramadol, (+)-M1 and was found to be useful for its pharmacodynamic profiling.     

Enantiospecific pharmacokinetics of metoprolol in CYP2D6 ultra-rapid metabolizers and correlation with exercise-induced heart rate

OBJECTIVE: Our objective was to study the enantioselective pharmacokinetics of metoprolol in CYP2D6 ultra-rapid metabolizers (UM) compared with extensive (EM) and poor (PM) metabolizers to quantify differential effects of metoprolol enantiomers on the beta1-adrenoreceptor blockade. METHODS: Twenty-nine healthy individuals were selected based on their CYP2D6 genotype, and 100 mg racemic metoprolol was administered. Plasma concentrations of R- and S-metoprolol and the metabolites SS-, SR-, RS-, and RR-hydroxymetoprolol were quantified by high-performance liquid chromatography. RESULTS: Mean (+/-SD) AUCs of S-metoprolol were 190 +/- 99 ng/ml.h in UMs, 366 +/- 158 in EMs, and 1,804 +/- 300 in PMs. For R-metoprolol, the AUCs were 127 +/- 72 ng/ml.h in UMs, 261 +/- 126 in EMs, and 1,746 +/- 319 in PMs. The concentrations of R-metoprolol and S-metoprolol, respectively, needed to obtain a half-maximum reduction in heart rate were estimated as 20 and 21 ng/ml in PMs, 11 and 17 ng/ml in EMs, and 7 and 11 ng/ml in UMs. CONCLUSION: A slight enantiopreference towards metabolism of R-metoprolol by CYP2D6 was observed in EMs and even more in the UM group, but the effect was far from being enantioselective.     

The influence of CYP2D6 phenotype on the clinical response of nebivolol in patients with essential hypertension

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * The variability in drug metabolism has been recognized as an important factor in the occurrence of adverse effects or lack of therapeutic efficacy. * The metabolism of the third-generation beta(1)-receptor antagonist nebivolol has been shown to be highly dependent on cytochrome P450 2D6 enzymatic activity in preclinical studies. WHAT THIS STUDY ADDS: * This paper assesses the role of a cytochrome P450 2D6 gene defect on the antihypertensive response to nebivolol in a clinical setting. * Despite significant differences in drug disposition, the chronic administration of nebivolol produced similar efficacy and tolerability in hypertensive patients either characterized as poor or extensive metabolizers of the drug. * The study offers insight into the relative contribution of nebivolol enantiomers in systemic blood pressure control. AIMS: Nebivolol is a beta(1)-adrenergic receptor antagonist with vasodilating properties used in the treatment of hypertension. It is administered as a racemic mixture (D- and L-nebivolol) and is highly metabolized by the cytochrome P-450 2D6 (CYP2D6). The purpose of this study was to determine the role of CYP2D6 phenotypes on the efficacy and tolerability of nebivolol during chronic administration to patients with essential hypertension. METHODS: Two hundred and eighteen patients were genotyped and phenotyped for CYP2D6 activity, allowing to find and match 14 poor metabolizers (PMs) with 23 extensive metabolizers (EMs). Patients took rac-nebivolol 5 mg daily for 12 weeks. Blood pressure (BP), heart rate, adverse events, plasma levels of the two enantiomers D- and L-nebivolol and their corresponding hydroxymetabolites were assessed. RESULTS: The metabolic disposition of nebivolol was enantioselective and highly influenced by CYP2D6 phenotypes. Mean steady-state plasma concentrations of D- and L-nebivolol were 10- and 15-fold greater in PMs than in EMs, respectively (P < 0.0001). Despite these differences in the pharmacokinetics of nebivolol, EMs and PMs displayed similar BP responses. Mean reductions in sitting systolic and diastolic BPs were -11/-10 +/- 9/4 mmHg in EMs and -11/-9 +/- 10/5 mmHg in PMs. Side-effects were mild to moderate and not different between groups. CONCLUSION: Polymorphisms in the gene encoding CYP2D6 significantly influenced the metabolism of nebivolol, but not its antihypertensive efficacy and tolerability. The similar clinical response between EMs and PMs could be explained by the contribution of active hydroxylated metabolites of nebivolol to its antihypertensive actions in EMs.     

Influence of donor and recipient genotypes on CYP2D6 phenotype after liver transplantation: a study of mutations CYP2D6*3 and CYP2D6*4

Objective: After liver transplantation (LT), genotypic differences between the recipient and the transplanted liver, medications and post-LT complications may all affect drug metabolism. We have studied the effect of two CYP2D6 mutations in the donor and the recipient on post-LT CYP2D6 phenotype. Method: The CYP2D6 phenotype was assessed in 48 patients before and after LT with debrisoquine or␣dextromethorphan. CYP2D6*3 (CYP2D6A) and CYP2D6*4 (CYP2D6B) mutations were detected in the donor and the recipient using polymerase chain reaction. Results: Before LT, 40 subjects were classified as extensive metabolisers (EM) and 8 as poor metabolisers (PM); after transplantation, 41 were EMs and 7 were PMs. Genotype and phenotype were in agreement in 100% of EMs and 40% of PMs. The low percentage of agreement in PMs could not be explained by severely altered liver function. The phenotype of 13 subjects was apparently changed by LT: 6 EMs became PMs and 7 PMs became EMs. All four subjects in whom genotype changed following LT had a corresponding change in phenotype: two EM subjects became PMs and two PM subjects became EMs. Conclusion: The low percentage of agreement in PMs may be partly explained by mutations other than CYP2D6*3 and CYP2D6*4. Nevertheless, our study shows that the CYP2D6 genotype of the donor controls the phenotype of the recipient of a liver transplantation. Received: 2 June 1997 / Accepted in revised form: 9 October 1997     

The impact of cytochrome P450-2D6 genotype on the use and interpretation of therapeutic drug monitoring in long-stay patients treated with antidepressant and antipsychotic drugs in daily psychiatric practice

PURPOSE: This retrospective follow-up study investigates whether cytochrome P450-2D6 (CYP2D6) genotype explains variability in plasma concentrations of psychotropic drugs in daily psychiatric practice. METHODS: The study population consisted of 62 hospitalised psychiatric patients genotyped for CYP2D6. Primary endpoint was the normalised plasma concentration ratio which was defined as the [measured concentration]/[mean therapeutic concentration] allowing comparison of plasma concentrations of different substrates. Secondary endpoint was a plasma concentration above the therapeutic range. The determinant was CYP2D6 genotype classified as ultrarapid metaboliser (UM), extensive metaboliser (EM), intermediate metaboliser (IM), or poor metaboliser (PM). The relation between CYP2D6 genotype and the normalised plasma concentration ratio was assessed with a linear mixed-effects model after adjustment for the Prescribed Daily Dose (PDD). The risk of having a plasma concentration above the therapeutic range was assessed with a logistic mixed-effects model. RESULTS: For antidepressants, CYP2D6 genotype PM (1.68 (95%CI: 1.01-2.28)) and IM (1.09 (95%CI: 0.77-1.29)) were associated with higher normalised plasma concentration ratios of antidepressants compared to EMs (0.56 (95%CI: 0.26-0.74)). In addition, the risk of a plasma concentration above the therapeutic range was increased for PMs (OR 33.1 (95%CI: 2.0-544.6)) and IMs (OR 8.2 (95%CI: 1.1-60.3)) relative to EMs using antidepressants. CYP2D6 genotype could not clearly explain variability in plasma concentrations of antipsychotics possibly due to a low frequency of therapeutic drug monitoring (TDM) in antipsychotics primarily metabolised by CYP2D6 in daily psychiatric practice. CONCLUSIONS: CYP2D6 genotype contributes to clinically relevant variability in plasma concentrations of antidepressants but probably not antipsychotics in daily clinical practice.     

Imipramine metabolism in relation to the sparteine and mephenytoin oxidation polymorphisms--a population study.

1. Sparteine and mephenytoin phenotyping tests were carried out in 327 healthy Danish subjects. Two weeks later each subject took 25 mg imipramine followed by urine collection for 24 h. The urinary content of imipramine, desipramine, 2-hydroxy-imipramine and 2-hydroxy-desipramine was assayed by h.p.l.c. 2. The medians of the hydroxylation ratios (i.e. 2-hydroxy-metabolite over parent compound) were 6 to 14 times higher in 300 extensive metabolizers of sparteine (EMs) as compared with 27 poor metabolizers (PMs), but none of the ratios separated the two phenotypes completely. 3. There were 324 EM of mephenytoin (EMM) and three PM (PMM) in the sample. The demethylation ratios between desipramine, 2-hydroxy-desipramine and their corresponding tertiary amines showed statistically significant correlations with the mephenytoin S/R isomer ratio (Spearman''s rs: -0.20 and -0.27, P < 0.05). 4. The demethylation ratios were higher in 80 smokers than in 245 non-smokers. This indicates that CYP1A2, which is induced by cigarette smoking, also catalyzes the N-demethylation of imipramine. 5. CYP2D6 genotyping was carried out by PCR in 325 of the subjects, and the D6-wt allele was amplified in 298 EMs, meaning that they were genotyped correctly. One PMs was D6-wt/D6-B, another PMs had the genotype D6-wt/ and hence both were misclassified as EMs. The remaining 25 PMs were D6-A/D6-B (n = 5), D6-B/ (n = 18) or D6-D/D6-D (no PCR amplification, n = 2).(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of active metabolites in dihydrocodeine effects

OBJECTIVE: The metabolism of dihydrocodeine to dihydromorphine, a high affinity mu-opioid receptor ligand in membrane homogenates, is catalyzed by CYP2D6. However, it is not clear whether an active CYP2D6 enzyme is required for opioid receptor-mediated effects in man after standard dihydrocodeine doses. METHODS: Whole cell opioid-receptor affinity and effects on cAMP accumulation of dihydrocodeine and its metabolites were determined in differentiated SH-SY5Y neuroblastoma cells. In a double-blind, 2-period, placebo-controlled randomized crossover pilot study the pharmacokinetics of dihydrocodeine (60 mg single dose) and its metabolites were examined in 5 phenotyped extensive (EMs) and 4 poor metabolizers (PMs) for CYP2D6, and pharmacodynamics were evaluated using a pain threshold model and dynamic pupillometry. RESULTS: Displacement binding and cAMP accumulation experiments showed clearly higher affinities (100- and 50-fold) and activities (180- and 250-fold) of dihydromorphine and dihydromorphine-6-glucuronide, respectively, whereas the other metabolites had similar or lower affinities and activities as compared to dihydrocodeine. The clinical study revealed no significant difference in plasma or urine pharmacokinetics between EMs and PMs for dihydrocodeine and its glucuronide. Dihydromorphine and its glucuronides were detectable in EMs only. A clear reduction of initial pupil diameters was observed up to 6 hours postdose in both PMs and EMs, with no obvious differences between CYP2D6 phenotypes. In the pain threshold model no effects were observed in either group. CONCLUSION: CYP2D6 phenotype has no major impact on opioid receptor-mediated effects of a single 60 mg dihydrocodeine dose, despite the essential role of CYP2D6 in formation of highly active metabolites.     

Impact of the <Emphasis Type="Italic">CYP2D6</Emphasis> genotype on steady-state serum concentrations of aripiprazole and dehydroaripiprazole

Objective Aripiprazole is an atypical antipsychotic drug which is metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). The aim of the present study was to investigate the impact of the CYP2D6 genotype on serum concentrations of aripiprazole (ARI) and to determine the sum of ARI and the active metabolite dehydroaripiprazole (DARI) in psychiatric patients. Methods Data on steady-state serum concentrations and the CYP2D6 genotypes of patients treated with ARI were extracted from a routine therapeutic drug monitoring database. The 62 patients included in the analysis were stratified into the following subgroups according to CYP2D6 genotype: *1/*1 (homozygous extensive metabolizers, EMs; n = 37), *1/*3–6 (heterozygous extensive metabolizers, HEMs; n = 17) and *3–6/*3–6 (poor metabolizers, PMs; n = 8). Dose-adjusted serum concentrations (C/D ratios) of ARI and ARI + DARI were compared between the subgroups. Results The median serum concentration of ARI was 1.7-fold higher in PMs than in EMs (45.5 vs. 26.3 nM/mg, p < 0.01). The observed serum concentration of the active sum of ARI + DARI was 1.5-fold higher in PMs than in EMs (53.9 vs. 37.0 nM/mg, p < 0.05). Numerical differences in serum concentrations between HEMs and EMs were less pronounced, but statistically significant for both ARI (p < 0.05) and ARI + DARI (p < 0.05). Conclusion The present study demonstrates that serum concentrations of both ARI and the active sum of ARI + DARI in psychiatric patients were significantly affected by CYP2D6 genotype. The observed differences in median C/D ratios indicate that PMs typically need 30–40% lower doses to achieve a similar steady-state serum concentration as EMs.     

Effects of clarithromycin on lansoprazole pharmacokinetics between CYP2C19 genotypes

AIMS: Lansoprazole is a substrate of CYP2C19 and CYP3A. The aim of this study was to compare the inhibitory effects of clarithromycin, an inhibitor of CYP3A on the metabolism of lansoprazole between CYP2C19 genotypes. METHODS: A two-way randomized double-blind, placebo-controlled crossover study was performed. Eighteen volunteers, of whom six were homozygous extensive metabolizers (EMs), six were heterozygous EMs and six were poor metabolizers (PMs) for CYP2C19, received two 6-day courses of either clarithromycin 800 mg or placebo daily in a randomized fashion with a single oral dose of lansoprazole 60 mg on day 6 in all cases. Plasma concentrations of lansoprazole and its metabolites, 5-hydroxylansoprazole and lansoprazole sulphone were monitored up to 24 h after dosing. RESULTS: During placebo administration, the mean AUC0, infinity of lansoprazole in homozygous EMs, heterozygous EMs and PMs were 4652 (95% CI, 2294, 7009) ng ml(-1) h, 8299 (4784, 11814) ng ml(-1) h and 25293 (17643, 32943) ng ml(-1) h (P < 0.001), respectively. Clarithromycin treatment significantly increased Cmax by 1.47-fold, 1.71-fold and 1.52-fold and AUC0, infinity of lansoprazole by 1.55-fold, 1.74-fold, and 1.80-fold in these genotype groups, respectively, whereas elimination half-life was prolonged only in PMs. The clarithromycin-mediated percent increase in pharmacokinetic parameters such as Cmax, AUC0, infinity or elimination half-life did not differ between the three CYP2C19 genotypes. CONCLUSIONS: The present study indicates that there are significant drug interactions between lansoprazole and clarithromycin in all CYP2C19 genotype groups probably through CYP3A inhibition. The bioavailability of lansoprazole might, to some extent, be increased through inhibition of P-glycoprotein during clarithromycin treatment.     

Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: Meta-analysis of data from genome-wide association studies

Cytochrome (CYP) P450 enzymes have a primary role in antidepressant metabolism and variants in these polymorphic genes are targets for pharmacogenetic investigation. This is the first meta-analysis to investigate how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects.CYP2C19 metabolic phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most common CYP2C19 functional polymorphisms (rs4244285 and rs12248560) in Caucasians. These polymorphisms were genotyped or imputed from genome-wide data in four samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod, PGRN-AMPS). Treatment efficacy was assessed by standardized percentage symptom improvement and by remission. Side effect data were available at weeks 2–4, 6 and 9 in three samples. A fixed-effects meta-analysis was performed using EM as the reference group.Analysis of 2558 patients for efficacy and 2037 patients for side effects showed that PMs had higher symptom improvement (SMD?=?0.43, CI?=?0.19–0.66) and higher remission rates (OR?=?1.55, CI?=?1.23–1.96) compared to EMs. At weeks 2–4, PMs showed higher risk of gastro-intestinal (OR?=?1.26, CI?=?1.08–1.47), neurological (OR?=?1.28, CI?=?1.07–1.53) and sexual side effects (OR?=?1.52, CI?=?1.23–1.87; week 6 values were similar). No difference was seen at week 9 or in total side effect burden. PMs did not have higher risk of dropout at week 4 compared to EMs. Antidepressant dose was not different among CYP2C19 groups.CYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs being relatively rare among Caucasians (～2%).     

Metabolic cytochrome P450 genotypes and assessment of individual susceptibility to lung cancer.

Three polymorphic cytochrome P450 genes that have attracted interest for their potential role in human pulmonary carcinogenesis, i.e. CYP1A1, CYP2D6 and CYP2E1, were studied in a population consisting of 106 lung cancer patients and 122 healthy controls. Polymorphism of the CYP2D6 gene encoding for debrisoquine hydroxylase was determined using XbaI restriction fragment length polymorphism (RFLP) analysis together with a PCR based method. All of the three most common presently known defective alleles of CYP2D6 were detected by this application. Subjects having genotypes either homozygous or heterozygous for the CYP2D6 wild type alleles were classified as extensive metabolizers (EMs) of debrisoquine whereas poor metabolizers (PMs) had two defective alleles. The PM individuals are thought to be less prone to develop lung cancer. The CYP1A1 and CYP2E1 genes were studied by RFLP analyses using Msp I and Dra I restriction enzymes, respectively, giving rise to two different sized hybridizable fragments in Southern blot analyses. In these RFPL analyses genotypes homozygous to the mutated allele have been presented as potent determinants of individual lung cancer risk. In the present study no association between polymorphic CYP1A1 and CYP2E1 genotypes and susceptibility to lung cancer was found. However, CYP2D6 polymorphism studies of the 122 healthy controls revealed seven poor metabolizer genotypes (5.7%), which compares well with the previously observed phenotypic distribution in the Finnish population, whereas only one PM genotype (1/106) was found among the lung cancer patients. These results agree with the previous suggestions that PMs of debrisoquine are less susceptible to lung cancer than EMs.     

Lack of interaction of milnacipran with the cytochrome p450 isoenzymes frequently involved in the metabolism of antidepressants

OBJECTIVE: To compare the pharmacokinetics of milnacipran in extensive metabolisers (EMs) and poor metabolisers (PMs) of sparteine and mephenytoin, and to assess the influence of multiple administrations of milnacipran on the activity of cytochrome P450 (CYP) isoenzymes through its own metabolism and through various probes, namely CYP2D6 (sparteine/dextromethorphan), CYP2C19 (mephenytoin), CYP1A2 (caffeine) and CYP3A4 (endogenous 6-beta-hydroxy-cortisol excretion). METHODS: Twenty-five healthy subjects, 12 EMs for both sparteine/dextromethorphan and mephenytoin, nine EMs for mephenytoin and PMs for sparteine/dextromethorphan (PM(2D6)) and four PMs for mephenytoin and EMs for sparteine/dextromethorphan (PM(2C19)) were administered milnacipran as a single 50 mg capsule on day 1 followed by a 50 mg capsule twice daily for 7 days. The pharmacokinetics of milnacipran and its oxidative metabolites were assessed after the first dose (day 1) and after multiple administration (day 8), and were compared for differences between CYP2D6 and CYP2C19 PMs and EMs. Metabolic tests were performed before (day -2), during (days 1 and 8) and after (day 20) milnacipran administration. RESULTS: Milnacipran steady state was rapidly achieved. Metabolism was limited: approximately 50% unchanged drug, 30% as glucuronide and 20% as oxidative metabolite (mainly F2800 the N-dealkyl metabolite). Milnacipran administration to PM2D6 and PM2C19 subjects did not increase parent drug exposure or decrease metabolite exposure. Milnacipran oxidative metabolism is not mediated through CYP2D6 or CYP2C19 polymorphic pathways nor does it significantly interact with CYP1A2, CYP2C19, CYP2D6 or CYP3A4 activities. CONCLUSION: Limited reciprocal pharmacokinetic interaction between milnacipran and CYP isoenzymes would confer flexibility in the therapeutic use of the drug when combined with antidepressants. Drug-drug interaction risk would be low, even if the combined treatments were likely to inhibit CYP2D6 and CYP2C19 isoenzyme activities.