Impact of CYP2D6*10 on H1-antihistamine-induced hypersomnia

Objective This study investigated the relevance of the cytochrome P450 (CYP) 2D6 genotype to the adverse drug reactions (ADRs) of H1-antihistamines and the level of sedation.Methods Japanese participants in a health screening program were asked to describe any past history of ADRs. Any subjects reporting ADRs induced by H1-antihistamines were then individually interviewed and defined as cases. Excessive daytime sleepiness, which had occurred in the cases as an H1-antihistamine-induced ADR, was assessed by the Epworth sleepiness scale (ESS), and an ESS score ≥12 was considered hypersomnia. CYP2D6*4, *5, *14, and *10 were genotyped by a panel of polymerase chain reaction techniques.Results Out of 2,074 participants, 100 cases (M:F = 37:63, mean age 51.9 ± 9.2 years) were eligible for analysis. The most common etiological drug was chlorpheniramine, which is the most frequently used H1-antihistamine in Japan. CYP2D6*10 allele and genotypes were more frequently found in the cases than in the healthy Japanese population in a large study (P < 0.005 and P = 0.039, respectively), but no difference was observed in the null alleles and genotypes. The ESS scores in 75 cases (M:F=25:50) who had experienced excessive daytime sleepiness were 9.5 ± 5.5 in men and 12.9 ± 6.1 in women (P < 0.001, cases vs. 34 subjects without symptoms; P = 0.001 men vs. women). The occurrence of hypersomnia increased as the number of CYP2D6 mutant alleles increased (P = 0.045).Conclusion The results suggest that the presence of the CYP2D6*10 allele is a risk factor for development of H1-antihistamine-induced ADRs in Japanese.     

CYP2D6 polymorphism in systemic lupus erythematosus patients

Objectives: To determine whether patients with idiopathic systemic lupus erythematosus (SLE) are associated with impaired CYP2D6 activity and to gain insight into whether there is an association between particular CYP2D6 genotypes and susceptibility to SLE, and whether CYP2D6 polymorphism is linked to any specific clinical features of SLE. Methods: Debrisoquine sulfate (10 mg p.o.) was given to 159 healthy volunteers and 39 idiopathic SLE patients. Genotypic assay was carried out in 80 healthy volunteers and 32 patients. A 10-ml blood sample was drawn for genotypic assay. Debrisoquine and 4-hydroxydebrisoquine were determined in 8-h urine samples. Blood samples were analysed for the presence of mutations in the CYP2D6 gene, by using polymerase chain reaction (PCR) specific for CYP2D6*3 and CYP2D6*4 alleles. Results: The metabolic ratio of debrisoquine to 4-hydroxydebrisoquine ranged from 0.01 to 86.98 in healthy subjects and from 0.02 to 96 in SLE patients. We observed the poor metabolizer(PM) debrisoquine phenotype in three of 39 patients with idiopathic SLE (7.6%) and five of 159 healthy subjects (3.1%). There was no significant difference in the frequency of PM phenotypes between idiopathic SLE and healthy subjects (Fisher's exact test, P = 0.19). No significant difference in the distribution of overall genotypes and allele frequencies were observed between the two groups. No significant relationships were found between specific clinical features and the overall genotype. Conclusion: The results of this study confirm that CYP2D6 activity is not impaired in SLE and that there is no association between SLE and phenotypic CYP2D6 status. The results also showed that there was no difference in the frequency of CYP2D6A and CYP2D6B alleles between controls and patients with SLE. Received: 14 May 1998 / Accepted in revised form: 19 October 1998     

Effects of CYP2D6 polymorphisms on neuroleptic malignant syndrome

Objective Neuroleptic malignant syndrome (NMS) is one of the most serious adverse reactions to antipsychotic medications. We accumulated data on Japanese NMS patients and, in a study designed to examine the effects of drug metabolism on the occurrence of NMS, tested the possibility of association between NMS and CYP2D6 polymorphisms. Methods We studied 53 patients who had experienced NMS and 112 healthy individuals. We determined what drugs the patients with NMS had been given and retrospectively identified candidates for drugs causing NMS. We screened the prevalence of CYP2D6 genotypes using polymerase chain reaction and restriction fragment length polymorphism analyses. Results The prevalence of *5 alleles in the group of all patients with NMS was higher than that in the controls, though this difference was not statistically significant (10.4% vs. 5.4%; P = 0.107; odds ratio (OR) 2.05; 95% confidence interval (CI) 0.87–4.80). No association was found between the frequency of *10 alleles and the occurrence of NMS. We found *4 and duplicated alleles in only one patient each among the patients with NMS. A total of 29 patients appeared to have developed NMS as a result of having taking CYP2D6 substrates. The prevalence of *5 alleles in these 29 patient was significantly higher than that in the controls (15.5% vs. 5.4%; P = 0.020; OR 3.25; 95% CI 1.30–8.13). Conclusion Our findings suggest that the CYP2D6*5 allele is likely to affect vulnerability to development of NMS.     

The impact of the CYP2D6 and CYP2C19 genotypes on venlafaxine pharmacokinetics in a Japanese population

Objective: The cytochrome P ₄₅₀ isozymes CYP2D6 and CYP2C19 exhibit genetic polymorphism in human, including a marked interethnic difference. As the functional status of the isozymes CYP2D6 and CYP2C19 have an impact on the pharmacokinetics of some antidepressants, we investigated whether the disposition of venlafaxine was affected by the CYP2D6 and CYP2C19 genotypes. Methods: Twenty-eight adult Japanese men in good health participated in this study. Genomic DNA was isolated from peripheral lymphocytes, and the CYP2D6 genotype was determined using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) analysis and XbaI-RFLP analysis. Subjects were categorized into the following four groups: group 1 CYP2D6*10/*10; group 2 CYP2D6*1/*10 and *2/*10; group 3 CYP2D6*1/*1, *1/*2 and *2/*2; and group 4 the other genotypes. Two defective CYP2C19 alleles (CYP2C19*2 and CYP2C19*3) were identified by means of PCR-RFLP analysis. Venlafaxine was administered orally following an overnight fast. Plasma concentrations of venlafaxine and O-desmethylvenlafaxine were monitored using high-performance liquid chromatography up to 24 h. Results: The peak plasma concentration and values of area under the concentration–time curve up to 24 h for venlafaxine were 298% and 453% higher for group 1 than group 3, and 91% and 120% higher for group 2 than for group 3, respectively. The homozygote for two defective alleles of CYP2C19 showed a higher concentration of venlafaxine within group 1 and group 2. Conclusion: The CYP2D6*10 allele and two CYP2C19 defective alleles, common in an Asian population, are the most likely genetic factors to use in determining interindividual differences in the pharmacokinetics of venlafaxine, although the results with respect to CYP2C19 are preliminary because of the few subjects used. Received: 6 July 1999 / Accepted in revised form 11 January 2000     

CYP2D6 and CYP2C19 genotypes in an elderly Swedish population

Objective: Eighty-three healthy elderly Swedish subjects (age 87 ± 4 years, mean ± SD, range 80–98 years) were genotyped with respect to the two genetic polymorphisms of oxidative drug metabolism, CYP2D6 and CYP2C19, using allele-specific polymerase chain reaction (PCR). A control population consisted of 248 younger unrelated healthy volunteers (age 31 ± 9 years, range 19–63 years) for CYP2D6, and 162 (age 30 ± 8 years, range 19–55 years) for CYP2C19. Results: No significant differences were found between the control groups and the elderly subjects with respect to the frequencies of the defect alleles CYP2D6*3, CYP2D6*4, CYP2C19*2 and CYP2C19*3. Neither were there any differences in the genotype frequencies, or the predicted phenotype frequencies. The study indicates that the CYP2D6 and CYP2C19 genotypes play no major role in the probability of reaching high age. Conclusion: No genetically determined differences in the pharmacokinetics of drugs metabolized by these two polymorphic enzymes are to be expected in the oldest age groups compared with younger adults. Received: 10 March 1998 / Accepted: 1 May 1998     

The pharmacokinetics of codeine and its metabolites in Blacks with sickle cell disease

Purpose  We conducted a prospective, open-label study in 54 adult subjects with sickle cell disease to determine the relationship between morphine concentrations, cytochrome P450 (CYP) 2D6 genotype, and clinical outcomes. Methods  A blood sample was obtained for genotyping and serial blood samples were drawn to measure codeine and its metabolites in the plasma before and after oral codeine sulfate 30mg. Codeine and its metabolites were measured by liquid chromatography-tandem mass spectrometry (LC-MS). CYP2D6 genetic testing included four single nucleotide polymorphisms (SNP) indicative of three variant alleles: *17 (1023T); *29 (1659A, 3183A); and *41 (2988A) alleles. Results  Thirty subjects (group I) had a mean (standard deviation) maximal morphine concentration of 2.0 (1.0) ng/ml. Morphine was not measurable in the remaining 24 subjects (group II). Nine (30%) subjects in group I and 11 (46%) subjects in group II carried a variant *17, *29, or *41 allele (p = 0.23); one (3%) subject in group I and 5 (21%) subjects in group II were homozygous for *17 or *29 allele (p = 0.07). Emergency room visits (group I 1.5 ± 1.8 vs. group II 2.1 ± 4.3, p = NS) did not differ based on metabolic status, but more hospital admissions (0.9 ± 1.4 vs. 2.2 ± 4.1, p = 0.05) were documented in patients with no measurable morphine concentrations. Conclusions  We conclude that Blacks with sickle cell disease without measurable plasma morphine levels after a single dose of codeine were not more likely to be a carrier of a single variant allele commonly associated with reduced CYP2D6 metabolic capacity; however, homozygosity for a variant CYP2D6 allele may result in reduced metabolic capacity. Furthermore, it appears that subjects without measurable morphine concentrations were more likely to be admitted to the hospital for an acute pain crisis. This study was supported in part by the Illinois Department of Public Health awarded to the Sickle Cell Center, Janssen Medical Affairs, LLC (FEN-EMR4007) and a Clinical Translational Science Award from the Center for Clinical Translational Science at the University of Illinois awarded to Dr. Stacy S. Shord and the General Clinical Research Center at the University of Illinois Medical Center at Chicago (NIH grant M01-RR-13987).     

Debrisoquine and S -mephenytoin hydroxylation polymorphisms in a Russian population living in Estonia

Objective: To investigate the CYP2D6 and CYP2C19 phenotypes and genotypes in a Russian population of Estonia. Methods: Two hundred and eighteen unrelated healthy subjects of Russian origin were studied. All participants took 10 mg debrisoquine and 100 mg S/R-mephenytoin for phenotyping. The CYP2D6 genotype was analysed by PCR amplification for the CYP2D6*3 and CYP2D6*4 alleles and subjects with S/R-mephenytoin ratios of greater than 0.5 were genotyped with respect to CYP2C19*2 and CYP2C19*3 alleles. Results: Seventeen subjects (7.8%) were classified as poor metabolisers of debrisoquine and 5 (2.3%) as poor metabolisers of S-mephenytoin. The frequency of CYP2D6*4 was 14.4% and that of CYP2D6*3 1.4%. Seven of 15 poor metabolisers of debrisoquine (47%) carried two defective CYP2D6 alleles (CYP2D6*3 or CYP2D6*4). Six of the 10 S-mephenytoin poor-metaboliser alleles (60%) carried either the CYP2C19*2 or CYP2C19*3. Conclusion: The frequencies of poor metabolisers of debrisoquine and S-mephenytoin among Russians were similar to those in other Caucasian populations. The CYP2D6 poor-metaboliser phenotype was predicted by PCR-based amplification for the CYP2D6*3 and CYP2D6*4 alleles with 47% accuracy. The frequency of the CYP2D6*4 allele was lower in Russians than in other Caucasian populations studied so far. Received: 17 February 1997 / Accepted in revised form: 27 June 1997     

Pharmacogenomics of CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP3A4, CYP3A5 and MDR1 in Vietnam

Aim  The aim of this study was to obtain pharmacogenetic data in a Vietnamese population on genes coding for proteins involved in the elimination of drugs currently used for the treatment of malaria and human immunodeficiency virus/acquired immunodeficiency syndrome. Method  The main polymorphisms on the cytochrome P450 (CYP) genes, CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP3A4 and CYP3A5, and the multi-drug resistance 1 gene (MDR1) were genotyped in 78 healthy Vietnamese subjects. Pharmacokinetic metrics were available for CYP2A6 (coumarin), CYP2C19 (mephenytoin), CYP2D6 (metoprolol) and CYP3As (midazolam), allowing correlations with the determined genotype. Results  In the CYP2 family, we detected alleles CYP2A6*4 (12%) and *5 (15%); CYP2B6*4 (8%), *6 (27%); CYP2C19*2 (31%) and *3 (6%); CYP2D6*4, *5, *10 (1, 8 and 44%, respectively). In the CYP3A family, CYP3A4*1B was detected at a low frequency (2%), whereas CYP3A5 *3 was detected at a frequency of 67%. The MDR1 3435T allele was present with a prevalence of 40%. Allele proportions in our cohort were compared with those reported for other Asian populations. CYP2C19 genotypes were associated to the S-4′-OH-mephenytoin/S-mephenytoin ratio quantified in plasma 4 h after intake of 100 mg mephenytoin. While CYP2D6 genotypes were partially reflected by the α-OH-metroprolol/metoprolol ratio in plasma 4 h after dosing, no correlation existed between midazolam plasma concentrations 4 h post-dose and CYP3A genotypes. Conclusions  The Vietnamese subjects of our study cohort presented allele prevalences in drug-metabolising enzymes that were generally comparable with those reported in other Asian populations. Deviations were found for CYP2A6*4 compared to a Chinese population (12 vs. 5%, respectively; P = 0.023), CYP2A6*5 compared with a Korean population (15 vs. <1%, respectively; P < 0.0001), a Malaysian population (1%; P < 0.0001) and a Chinese population (1%; P < 0.0001); CYP2B6*6 compared with a Korean population (27 vs. 12%; P = 0.002) and a Japanese population (16%; P = 0.021). Pharmacokinetic metrics versus genotype analysis reinforces the view that the predictive value of certain globally common variants (e.g. CYP2D6 single nucleotide polymorphisms) should be evaluated in a population-specific manner.     

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.     

Serum concentrations of venlafaxine and its metabolites O-desmethylvenlafaxine and N-desmethylvenlafaxine in heterozygous carriers of the CYP2D6*3, *4 or *5 allele

Objective Increased systemic exposure of the antidepressant venlafaxine and increased risk of side effects has previously been observed in patients with defective CYP2D6 function [poor metabolisers (PMs)]. The aim of this study was to evaluate venlafaxine pharmacokinetics in carriers of one functional and one defective CYP2D6 allele [heterozygous extensive metabolisers (HEMs)]. Methods Data was collected retrospectively from a therapeutic drug-monitoring database. All CYP-genotyped patients with steady-state serum concentration measurements of venlafaxine and metabolites were included in the study. Patients were divided in groups: *1/*1 [homozygous extensive metabolisers (EMs)], *1/*3, *4 or *5 (HEMs) and *4/*4 (PMs). Dose-adjusted serum concentrations of venlafaxine, O-desmethylvenlafaxine, N-desmethylvenlafaxine, and the metabolic ratio (O-desmethylvenlafaxine/venlafaxine) were compared between the different genotype groups. Results The sum of venlafaxine and O-desmethylvenlafaxine serum concentrations was not significantly different between genotype groups. Metabolic ratio was 50% lower in HEMs (n = 18) than in EMs (n = 20) (p < 0.05). Serum concentration of N-desmethylvenlafaxine was 5.5-fold higher in HEMs (p < 0.01) and 22-fold higher in PMs (p < 0.001) than in EMs. Conclusion The study showed a shift in the metabolic pathway resulting in substantially higher levels of N-desmethylvenlafaxine in HEMs than in EMs. The metabolic pattern of venlafaxine in HEMs was similar to previous observations in PMs and possibly represents an increased risk of venlafaxine-related side effects in HEM patients.     

Non-response to maprotiline caused by ultra-rapid metabolism that is different from CYP2D6?

Case: We are reporting about a patient with major depression who failed to respond to pharmacotherapy due to ultra-rapid metabolism of maprotiline. Under daily oral doses of 175 mg maprotiline, the patient's metabolic ratio (MR) for maprotiline in plasma was 9.2 (expected MR_p: 2.4) and the clearance of maprotiline (CL_M) was 4190 ml · min⁻¹ (expected CL_M = 1220 in extensive metabolisers of CYP2D6). Results: The patient's MR_urine for sparteine was 0.5, which is within the range for extensive metabolisers of CYP2D6. Genotyping did not show a duplication of the CYP2D6L allele. The patient's caffeine half-life was 10 h, thus, precluding ultra-rapid metabolism for CYP1A2. The therapeutic regimen was changed to coadministration of 200 mg maprotiline and 20 mg fluoxetine once per day in order to inhibit metabolism via CYP2D6. Subsequently, MR_p of maprotiline (4.9) and CL_M were reduced (1900 ml · min⁻¹; expected CL_M in poor metabolisers: of CYP2D6 364). This regimen improved the clinical outcome of the underlying disease. Conclusion: We conclude that for the non-response seen with maprotiline, P450 isozymes other than CYP2D6 or CYP1A2 are responsible. As CYP2C19 is involved in the metabolism of a number of tricyclic antidepressants it may be a candidate for ultra-rapid metabolism in this patient. Received: 11 October 1996 / Accepted in revised form: 6 February 1997     

Absolute bioavailability and metabolism of omeprazole in relation to CYP2C19 genotypes following single intravenous and oral administrations

Objective The aim of this study was to evaluate the absolute bioavailability and the metabolism of omeprazole following single intravenous and oral administrations to healthy subjects in relation to CYP2C19 genotypes. Methods Twenty subjects, of whom 6 were homozygous extensive metabolizers (hmEMs), 8 were heterozygous EMs (htEMs) and 6 were poor metabolizers (PMs) for CYP2C19, were enrolled in this study. Each subject received either a single omeprazole 20 mg intravenous dose (IV) or 40 mg oral dose (PO) in a randomized fashion during 2 different phases. Results Mean omeprazole AUC (0,∞) was 1164, 3093 and 10511 ng h/mL after PO, and 1435, 2495 and 6222 ng h/mL after IV in hmEMs, htEMs and PMs, respectively. Therefore, the absolute bioavailability of omeprazole in PMs was significantly higher than that in hmEMs (p < 0.001) and htEMs (p < 0.001). Hydroxylation metabolic indexes after IV and PO were significantly lower in PMs than in hmEMs (p < 0.001) and htEMs (p < 0.001), and was correlated with the absolute bioavailability (p < 0.0001 for both IV and PO). Sulfoxidation metabolic index after IV was significantly different between the CYP2C19 genotypes, whereas no difference was found after a single oral dose. Conclusion This study indicates that the absolute bioavailability of omeprazole differs among the three different CYP2C19 genotypes after a single dose of omeprazole orally or intravenously. Hydroxylation metabolic index of omeprazole may be mainly attributable to the genotype of CYP2C19. As for the sulfoxidation metabolic index after a single oral dose, intestinal CYP3A may be contributed to omeprazole metabolism.     

Lack of polymorphism of the conversion of losartan to its active metabolite E-3174 in extensive and poor metabolizers of debrisoquine (cytochrome P450 2D6) and mephenytoin (cytochrome P450 2C19)

Objective: Losartan was given to subjects with known phenotypes of the polymorphic enzymes CYP2D6 and CYP2C19 to study any possible influence on the metabolism of the drug. Methods: Plasma concentrations of losartan and E-3174 were studied after oral intake of 50 mg losartan in 24 healthy, male, Swedish Caucasian subjects who were extensive or poor metabolizers (EM/PM) of debrisoquine [cytochrome P450 2D6 (CYP2D6)] or mephenytoin [cytochrome P450 2C19 (CYP2C19)]. Results: The areas under the curve (AUC_∞) of losartan and E-3174 did not differ between poor and extensive metabolizers of debrisoquine or mephenytoin, respectively. Conclusion: About 14% of the antihypertensive drug losartan is metabolized to the active carboxylic acid metabolite E-3174, which contributes to the effect of losartan. The present study suggests that CYP2D6 and CYP2C19 are not involved to any major extent in the in vivo conversion of losartan to E-3174. Received: 21 April 1998 / Accepted in revised form: 16 December 1998     

Relationship between fluvoxamine pharmacokinetics and CYP2D6/CYP2C19 phenotype polymorphisms

Objective: The purpose of this study was to investigate whether the disposition of fluvoxamine is associated with the CYP2D6 and CYP2C19 phenotype polymorphisms. Methods: The serum concentration of fluvoxamine was followed for 48 h after oral administration of a single dose of 50 mg fluvoxamine to five poor metabolizers of the CYP2D6 test drug dextromethorphan, five poor metabolizers of the CYP2C19 test drug mephenytoin, and five extensive metabolizers of both test drugs. Results: Poor metabolizers of dextromethorphan had significantly higher areas under the serum concentration-time curve than extensive metabolizers of dextromethorphan (mean 1.31 vs 1.00 μmol · h · l⁻¹). There were no differences between poor and extensive metabolizers of mephenytoin (mean, 1.00 vs 1.15 μmol · h · l⁻¹). Conclusion: The results are consistent with a possible minor to moderate role of CYP2D6, but not CYP2C19, in fluvoxamine metabolism. Received: 25 April 1996 / Accepted in revised form: 12 November 1996     

Metabolism of carteolol by cDNA-expressed human cytochrome P450

Objectives: To determine human cytochrome P450 isoform(s) (CYPs) involved in the metabolism of carteolol, the biotransformation of the compound was investigated in vitro using ten isoforms of human cytochrome P450 expressed in human AHH-1 TK ± cell lines. In addition, the inhibitory effects of carteolol on the activities of important CYP isoforms, namely, CYP1A2, 2C9, 2C19, 2E1, and 3A4, were examined. Results: Carteolol was metabolised to 8-hydroxycarteolol by CYP 2D6 with K_M and V_max values of 183 μmoles · l⁻¹ and 26.09 pmol · min⁻¹ · pmol⁻¹ P450, respectively. CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1 and 3A4 were not involved in the metabolism of the compound. CYP2D6-mediated carteolol 8-hydroxylase activity was inhibited by quinidine, propranolol, nortriptyline, dextromethorphan, sparteine, bufuralol, and biperiden. Biperiden competitively inhibited the catalytic reaction with a K_i value of 0.45 μmoles · l⁻¹. Carteolol did not affect the following catalytic reactions:␣CYP1A2-mediated (R)-warfarin 6-hydroxylation, CYP2C9-mediated tolbutamide methylhydroxylation, CYP2C19-mediated (S)-mephenytoin 4-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, and CYP3A4-mediated testosterone 6β-hydroxylation. Conclusion: 8-Hydroxylation is the only cytochrome P450-catalyzed metabolic reaction of carteolol by its expressed microsomes, and CYP2D6 is the principal isoform of the enzyme involved in the catalytic reaction. Carteolol has neither stimulative nor inhibitory effects on CYP1A2, 2C9, 2C19, 2E1, and 3A4 activities. Received: 17 December 1996 / Accepted in revised form: 11 March 1997     

<Emphasis Type="Italic">CYP2C9</Emphasis> genotype and pharmacodynamic responses to losartan in patients with primary and secondary kidney diseases

Background  Losartan is used for anti-proteinuric as well as blood pressure effects in chronic kidney disease (CKD). It is metabolized by cytochrome P450 (CYP) 2C9 to active E-3174. Single nucleotide polymorphisms in CYP2C9 that reduce catalytic activity could reduce clinical benefits. Aim  The study aims were to determine whether CYP2C9 variant alleles (*2 and *3) altered urinary protein excretion, glomerular filtration rate, and blood pressure in Caucasian patients prescribed losartan. Methods  Differences between baseline and 6-month follow-up outcomes were compared by CYP2C9 genotypes in 59 patients using unpaired t test or Mann–Whitney U test. Results  Primary renal disease patients had a trend toward less favorable antiproteinuric response (−31.7 ± 156 vs. −125 ± 323%;  p = 0.123) when carrying variant alleles. Patients with secondary renal diseases had less favorable diastolic blood pressure (9.8 ± 16.0 vs. −3.2 ± 10.6 mmHg; p = 0.043) and systolic blood pressure (16.2 ± 27.1 vs. −5.5 ± 17.5 mmHg; p = 0.044) with CYP2C9 variants. Conclusion  These preliminary results suggest a possible influence of CYP2C9 genotype on proteinuria and blood pressure in Caucasian CKD patients treated with losartan.     

The influence of cytochrome P450 1A1 and glutathione S-transferase M1 genotypes on biomarker levels in coke-oven workers

The present study has the aim of evaluating gene-environment interaction on the levels of different biomarkers in coke-oven workers exposed to PAH. In order to assess whether the levels of some biomarkers (PAH-DNA adducts, nitro-PAH adducts to Hb and MN frequency) could be modulated by the genetic metabolic polymorphisms for CYP1A1 and GSTM1, we analysed in 76 coke-oven workers and 18 controls the CYP1A1 (MspI and Ile/Val sites) and the GSTM1 genotypes by a PCR assay. In individuals with shared set-up of CYP1A1 or GSTM1 genotypes, we analysed how the specified biomarkers correlated with total PAH exposure (urinary levels of 1-hydroxypyrene) both by a stratified analysis and logistic regression modelling. Statistically significant (P = 0.03 and P = 0.01) higher percentages of the more susceptible GSTM1− subjects compared to the GSTM1+ subjects and of the more susceptible CYP1A1 Ile/Val individuals compared to the CYP1A1 Ile/Ile individuals were detected for high levels of PAH-DNA adducts in the high exposure group (namely high levels of 1-OHP). A statistically significant association was observed between increased PAH-DNA adduct levels and the more susceptible GSTM1- genotype (P.O.R. = 4.18, P = 0.03) in a logistic regression modelling and a significant interaction between PAH exposure and GSTM1-genotype was found for PAH-DNA adducts. No effect of these metabolic genotypes was observed for MN frequency and nitro-PAH adducts to Hb. In conclusion, a gene-environment interaction between PAH exposure and two metabolic genotypes involved in activation (CYP1A1) and detoxification (GSTM1) of PAHs, respectively, has been identified. Received: 21 July 1999 / Accepted: 26 July 1999     

Pharmacogenetic characteristics of patients with complicated phenprocoumon dosing

Purpose  Anticoagulation therapy with coumarins necessitates a strict individualization of dosing. Whereas the impacts of the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) polymorphisms on warfarin dosing are clearly established, the role of these genetic variants on dosing and the safe use of phenprocoumon are less well investigated and, to a certain degree, controversial. Methods  We studied the most frequent functional polymorphisms of VKORC1, CYP2C9, and CYP3A5 in 60 consecutive patients demonstrating complicated phenprocoumon-mediated anticoagulation and in 120 controls. Results  The frequencies of the less active VKORC1 haplotype A-group alleles (p < 0.0001) and of CYP2C9 genotypes with two variant alleles (p = 0.035) were higher in the patient cohort than in the control group, while the frequency of patients carrying only one variant CYP2C9 allele was unchanged relative to the control subjects (RR 1.2; p = 0.49). Conclusion  The data suggest a fundamental role of VKORC1 haplotypes and a minor role of CYP2C9 variants in the anticoagulation property of phenprocoumon.     

Impact of genotype-predicted CYP2D6 metabolism on clinical effects and tolerability of metoprolol in patients after myocardial infarction – a prospective observational study

The β-1 adrenergic receptor blocker metoprolol is primarily metabolized by the polymorphic enzyme cytochrome P 450 2D6 (CYP2D6), an enzyme with substantial genetic heterogeneity. Our purpose was to investigate the impact of CYP2D6 metabolism on clinical effects and tolerability of metoprolol in patients after myocardial infarction (MI). We included 136 patients with MI discharged on treatment with metoprolol with a recommendation to the general practitioner (GP) to increase the metoprolol dose up to 200 mg/day within 2 months if possible. At follow-up, metoprolol dosage after up-titration, metoprolol steady-state trough plasma concentrations, hemodynamic parameters, potential metoprolol-induced adverse drug reactions and number of visits to the GP were measured. CYP2D6 genotyping including the reduced-function variant alleles CYP2D6*9, CYP2D6*10 and CYP2D6*41 was performed after end of follow-up. According to the genotype-defined CYP2D6 phenotypes, 30% of the patients were metoprolol extensive metabolizers (EMs), 55% intermediate metabolizers (IMs) and 13% poor metabolizers (PMs; carriers of non-coding and reduced-function variant included). Dose-adjusted metoprolol trough concentrations were significantly higher in IM (2-fold) and PM (6.2-fold) groups vs. the EM group (p < 0.001). Only 35% of patients in the PM group achieved the primary end point, i.e. reaching at least 85% of the expected maximum heart rate (HR) during exercise, compared with 78% in the EM group (p < 0.01), and maximum observed HR at exercise was significantly lower in the PM group vs. the EM group (129 ± 5 vs. 142 ± 2 bpm, p < 0.007). In contrast, metoprolol maintenance dose, blood pressure, exercise capacity, number of visits at the GP and frequency and severity of self-reported potential metoprolol-related adverse drug reactions were not significantly different between the groups. Using a comprehensive CYP2D6 genotyping panel, the present study demonstrates a > 6-fold increase of dose-adjusted plasma metoprolol trough concentration in CYP2D6 PMs vs. EMs with a parallel lower increase in achieved maximum HR during exercise but without association between genotype and frequency or severity of self-reported adverse drug effects. This may indicate that CYP2D6 PMs potentially could benefit of the increased plasma concentration per dose in a naturalistic setting.