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ABSTRACT: The nonsteroidal anti-inflammatory drug diclofenac is extensively metabolized by cytochrome P450 (CYP) enzymes, mainly by CYP2C9. Our objective was to study the effect of voriconazole, a potent inhibitor of several CYP enzymes, on the pharmacokinetics of diclofenac. This study had a two-way, open, crossover design and included 10 healthy Caucasian male subjects. In the control phase, the subjects ingested a single 50-mg oral dose of diclofenac. In the voriconazole phase, the subjects ingested voriconazole 400 mg twice daily on the first day and 200 mg twice daily on the second day, and 50 mg diclofenac was given 1 h after the last dose of voriconazole. Plasma diclofenac concentrations were determined for up to 24 h post-dose. In the voriconazole phase, the area under the plasma concentration-time curve of diclofenac was 178% (95% CI 143-212%; P < 0.001) and the peak plasma concentration was 214% (95% CI 128-300%; P < 0.05) of the respective control value. Voriconazole did not affect significantly the elimination half-life or time to maximum concentration of diclofenac. The renal clearance of diclofenac was decreased by 47% (95% CI -76% to -16%; P < 0.01) by voriconazole. In conclusion, voriconazole increased exposure to diclofenac, probably mainly by inhibition of its cytochrome P450 (CYP)-mediated metabolism. The inhibition of CYP2C9, and to some extent that of CYP3A4 and CYP2C19 enzymes during the first-pass metabolism of diclofenac seems to be involved in the interaction. The clinical importance of the interaction between voriconazole and diclofenac remains to be studied, but lower doses of diclofenac may be adequate for patients receiving voriconazole.
Fundamental and Clinical Pharmacology 12/2007; 21(6):651-6. · 1.80 Impact Factor
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ABSTRACT: The objective of this study was to investigate the genetic polymorphism of selected cytochrome P450 (CYP) enzymes and ABCB1 (encoding P-glycoprotein) of central importance with regard to the disposition of clinically used drugs in the Finnish population and to compare the results to pre-existing data from Caucasian populations. A random sample of 449 Finns was studied. Single nucleotide polymorphisms (SNPs) were genotyped using blood-derived genomic DNA and 5'-nuclease assays. We found that the allele frequencies of CYP1A2 SNP g.-163C>A, CYP2C8*3, CYP2C9*2, CYP2C9*3 and CYP2C19*2 were similar to those seen in other Caucasian populations. However, the allelic frequency of the variant ABCB1 SNP c.3435C>T allele was lower than previously reported. The frequency of the homozygous CYP3A5*1 expression was significantly higher than expected based on Hardy-Weinberg calculations (observed n = 8 vs. expected n = 3, P = 0.01). Other genotype frequencies corresponded to the expected values. The strong linkage between the CYP2C8*3 and the CYP2C9*2 alleles was confirmed in this study and the number of individuals with the rare haplotype CYP2C8*3*3/CYP2C9*2*2 was higher than expected. We conclude that the frequency of mutated CYP alleles in Finns were in agreement with earlier findings in Caucasian populations, but a lower frequency of the ABCB1 variant allele 3435T corresponding to that reported in Asian populations was found. The higher than expected frequency of the CYP3A5*1*1 genotype and the CYP2C8*3*3/CYP2C9*2*2 haplotype may influence the response to treatment with drugs metabolized by these enzymes.
Fundamental and Clinical Pharmacology 09/2007; 21(4):379-86. · 1.80 Impact Factor
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ABSTRACT: To investigate the effect of kidney disease on bupropion pharmacokinetics and on cytochrome P450 (CYP) 2B6 activity as measured by bupropion hydroxylation.
In an open parallel group study, 17 healthy, nonsmoking subjects and 10 patients with impaired kidney function received a single 150 mg oral dose of sustained release bupropion. Plasma concentrations of bupropion and its metabolites were measured for up to 72 h. Subjects were genotyped for the CYP2B6 SNPs 1459 C>T, 785 A>G and 516 G>T.
Bupropion AUC was 126% higher (P < 0.0001, 95% CI +72%, +180%), C(max) 86% higher (P = 0.001, 95% CI +40%, +131%), CL/F 63% lower (P = 0.001, 95% CI -29%, -96%), and t(1/2) 140% longer (P = 0.001, 95% CI +76%, +204%) in renally impaired patients. However, only minor changes were detected in the concentrations of the metabolites. In renally impaired subjects the hydroxybupropion : bupropion AUC ratio was decreased by 66% (P = < 0.0001, 95% CI -19%, -114%) and the hydrobupropion : bupropion AUC ratio by 69% (P = 0.001, 95% CI +8%, -146%) compared with controls.
The CL/F of bupropion was significantly lower in subjects with renal impairment. Because the principal metabolites of bupropion possess similar pharmacological activity to the parent compound, dosage recommendations for patients with renal impairment cannot be given. A direct effect of renal impairment on CYP2B6 activity could not be demonstrated by the present study design.
British Journal of Clinical Pharmacology 08/2007; 64(2):165-73. · 2.96 Impact Factor
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ABSTRACT: The prodrug cyclophosphamide (CPA) is activated by cytochrome P450 (CYP) enzymes. CPA is one of the corner stones in all cancer treatment. We have studied the effect of repeated doses of CPA given at different time intervals on the mRNA, protein levels, and enzyme activity of CYPs in rats.
Two groups of animals (A-75 and A-150) were treated with four doses of CPA (75 and 150 mg/kg, respectively) at short time intervals (6 h). The third group of animals (B-150) was treated with 150 mg/kg at 24-h intervals. Three animals were killed 30 min after administration, and three animals immediately before the next dose.
CYP2B1 and CYP2B2 mRNAs were significantly induced at 6 h after each dose in group A-75 (maximum of 2100-fold and 60-fold after the third dose, respectively), whereas the mRNA levels measured at 6 h postadministration in group A-150 were 1,490-fold and 36-fold after the second dose. In group B-150, no significant induction of mRNA levels was observed. CYP2B1 and CYP2B2 protein levels also increased with increased mRNAs. Plasma levels of 4-hydroxy-CPA measured at 30 min after dose correlated well with the increase in protein levels.
Up-regulation of CYP2B mRNA, with a concomitant increase in protein expression and activity, were observed after repeated administration of low doses of CPA compared with that found using higher doses, possibly due to toxicity counteracting induction. These results may help in designing more effective dosing schedules for CPA.
Clinical Cancer Research 08/2007; 13(14):4218-24. · 7.74 Impact Factor
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ABSTRACT: Our objective was to investigate the expression of different cytochromes P450 3A (CYP3A4, CYP3A5, and CYP3A7) and P-glycoprotein (ABCB1) genes along the human large intestine in paired tumour and normal samples. Real-time reverse transcriptase-polymerase chain reaction was used to measure CYP3A4-, CYP3A5-, CYP3A7- and ABCB1-specific mRNA expression, and Western blot analysis was used to measure membrane protein levels of CYP3A4/7, CYP3A5 and P-glycoprotein. Levels of mRNA and membrane protein fractions in the large intestine were compared with those of normal human liver. The mRNA expressions of CYP3A4, CYP3A5, CYP3A7 and ABCB1 in the large intestine were found to be highly variable, but overall the levels were significantly lower than those measured in liver (P < 0.0001, P < 0.001, P < 0.0001 and P < 0.01, respectively). At the membrane protein level, CYP3A4/7 was detected in all large intestine samples examined and the levels were substantially higher than those of the liver (P < 0.01). Although expression of CYP3A5 was detected in all large intestine samples, in most the levels were too low to allow quantification. P-glycoprotein was readily detected at levels slightly higher than those of liver (P < 0.05). Comparison between paired samples of normal and tumour in large intestine showed no significant differences in either the mRNA or membrane protein levels of these genes. In conclusion, this work suggests a potential role of the large intestine in the absorption and metabolism of xenobiotics and nutrients and no difference in the CYP3A and P-glycoprotein membrane protein fractions and mRNA expression between normal and tumour tissues.
Basic & Clinical Pharmacology & Toxicology 05/2007; 100(4):240-8. · 2.18 Impact Factor
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ABSTRACT: Our objective was to investigate the expression of different cytochromes P450 3A (CYP3A4, CYP3A5, and CYP3A7) and P-glycoprotein (ABCB1) genes along the human large intestine in paired tumour and normal samples. Real-time reverse transcriptase-polymerase chain reaction was used to measure CYP3A4-, CYP3A5-, CYP3A7- and ABCB1-specific mRNA expression, and Western blot analysis was used to measure membrane protein levels of CYP3A4/7, CYP3A5 and P-glycoprotein. Levels of mRNA and membrane protein fractions in the large intestine were compared with those of normal human liver. The mRNA expressions of CYP3A4, CYP3A5, CYP3A7 and ABCB1 in the large intestine were found to be highly variable, but overall the levels were significantly lower than those measured in liver (P < 0.0001, P < 0.001, P < 0.0001 and P < 0.01, respectively). At the membrane protein level, CYP3A4/7 was detected in all large intestine samples examined and the levels were substantially higher than those of the liver (P < 0.01). Although expression of CYP3A5 was detected in all large intestine samples, in most the levels were too low to allow quantification. P-glycoprotein was readily detected at levels slightly higher than those of liver (P < 0.05). Comparison between paired samples of normal and tumour in large intestine showed no significant differences in either the mRNA or membrane protein levels of these genes. In conclusion, this work suggests a potential role of the large intestine in the absorption and metabolism of xenobiotics and nutrients and no difference in the CYP3A and P-glycoprotein membrane protein fractions and mRNA expression between normal and tumour tissues.
Basic & Clinical Pharmacology & Toxicology 03/2007; 100(4):240 - 248. · 2.18 Impact Factor
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ABSTRACT: The aim of this study was to investigate the effect of inflammation on the gene expression of three cytochrome P450's (CYP) and P-glycoprotein (P-gp) in the rectal and colonic mucosa in patients with proctitis.
Biopsies were obtained from inflamed and normal mucosa in association with routine sigmoidoscopy in patients with proctitis. The biopsies were snap-frozen in liquid nitrogen. Real time PCR (polymerase chain reaction) was used for quantitative analyses of mRNA specific for the CYP2E1, CYP3A4 and CYP3A5 gene and the MDR1 genes. Values were normalised based on gene expression of beta-actin to enable comparisons between samples.
The gene expression of CYP2E1 and CYP3A4 was lower in mucosa with severe inflammation vs normal mucosa (p<0.05). For CYP3A5 and P-gp there was no significant difference when comparing normal and inflammatory changed mucosa.
Our study suggests that at least for some of the CYP enzymes the expression decreases in response to the inflammatory process in the gastrointestinal tract.
Upsala journal of medical sciences 01/2007; 112(3):303-12. · 0.73 Impact Factor
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ABSTRACT: Earlier evidence suggests that melatonin is almost exclusively metabolised by CYP1A2 and could serve as a probe drug for CYP1A2 phenotyping. However, caffeine inhibits the metabolism of melatonin by CYP1A2 and dietary caffeine could be a potential confounder for the measurement of CYP1A2 activity with melatonin. We undertook a 3-phase cross-over study in 12 healthy volunteers to examine whether caffeine (200 mg single dose), taken 12 hr or 24 hr prior to melatonin intake, would affect the results of CYP1A2 phenotyping results as assessed by a spot sample melatonin concentration 1.5 hr after intake of 6 mg of melatonin orally. In addition we examined the influence of the CYP1A2*1F polymorphism on the phenotyping results by combining the present material with another 12 persons from a previous study. Caffeine, co-administered 12 or 24 hr prior to melatonin intake, did not have any significant effect on the 1.5 hr melatonin concentration (P=0.086 for ANOVA), but in two volunteers about 4 times increase in melatonin concentration was observed after caffeine intake 12 hr (but not 24 hr) before phenotyping with melatonin. Also, individuals homozygous for the CYP1A2*1A allele had clearly higher 1.5 hr melatonin concentration compared with the *1F/*1F or the *1F/*1A genotypes. Abstinence from caffeine for 24 hr prior to melatonin intake should be enough to overcome the possible confounding effect of caffeine on the CYP1A2 phenotyping with melatonin. Also, melatonin may be a sensitive probe to detect phenotypic differences with regard to CYP1A2*1F polymorphism. Melatonin might be, thus, advantageous for CYP1A2 phenotyping compared to the standard probe caffeine.
Basic & Clinical Pharmacology & Toxicology 11/2006; 99(4):300-4. · 2.18 Impact Factor
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ABSTRACT: Our objective was to study the effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of S-(+)- and R-(-)-ibuprofen. Twelve healthy male volunteers took a single oral dose of 400 mg racemic ibuprofen in a randomized order either alone, after ingestion of voriconazole at 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after ingestion of fluconazole at 400 mg on the first day and 200 mg on the second day. Ibuprofen was ingested 1 h after administration of the last dose of voriconazole or fluconazole. Plasma concentrations of S-(+)- and R-(-)-ibuprofen were measured for up to 24 h. In the voriconazole phase, the mean area under the plasma concentration-time curve (AUC) of S-(+)-ibuprofen was 205% (P < 0.001) of the respective control value and the mean peak plasma concentration (C(max)) was 122% (P < 0.01) of the respective control value. The mean elimination half-life (t(1/2)) was prolonged from 2.4 to 3.2 h (P < 0.01) by voriconazole. In the fluconazole phase, the mean AUC of S-(+)-ibuprofen was 183% of the control value (P < 0.001) and its mean C(max) was 116% of the control value (P < 0.05). The mean t(1/2) of S-(+)-ibuprofen was prolonged from 2.4 to 3.1 h (P < 0.05) by fluconazole. The geometric mean S-(+)-ibuprofen AUC ratios in the voriconazole and fluconazole phases were 2.01 (90% confidence interval [CI], 1.80 to 2.22) and 1.82 (90% CI, 1.72 to 1.91), respectively, i.e., above the bioequivalence acceptance upper limit of 1.25. Voriconazole and fluconazole had only weak effects on the pharmacokinetics of R-(-)-ibuprofen. In conclusion, voriconazole and fluconazole increased the levels of exposure to S-(+)-ibuprofen 2- and 1.8-fold, respectively. This was likely caused by inhibition of the cytochrome P450 2C9-mediated metabolism of S-(+)-ibuprofen. A reduction of the ibuprofen dosage should be considered when ibuprofen is coadministered with voriconazole or fluconazole, especially when the initial ibuprofen dose is high.
Antimicrobial Agents and Chemotherapy 06/2006; 50(6):1967-72. · 4.84 Impact Factor
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ABSTRACT: The non-nucleoside reverse transcriptase inhibitor efavirenz is mainly metabolised by the polymorphic cytochrome P450 enzyme CYP2B6. Genomic DNA from four subjects in a group of 51 patients being treated with efavirenz and having surprisingly high plasma concentrations were screened by direct sequencing for mutations in the CYP2B6 gene. Four exonic single nucleotide polymorphisms (SNPs), 516G > T, 714G > A, 785A > G and 983T > C, and eight intronic SNPs were identified. Haplotype analysis revealed that 983T > C was linked with 785A > G defining a novel allele, CYP2B6*16. This allele was present in totally five of the patients. The CYP2B6.16 cDNA was expressed in yeast and HEK293 cells and significantly less protein was formed compared to the wild-type cDNA, in both heterologous systems. By contrast, the catalytic activity of the enzyme variant was not different from the CYP2B6.1 enzyme, using bupropion as a probe substrate. The CYP2B6*16 allele was not found in Swedes, was present at 4% frequency among Turks, but was common among Africans. The steady-state level of efavirenz was significantly higher in the five carriers of CYP2B6*16, being of African origin, compared to the other patients. Higher efavirenz concentrations were also seen in carriers of 516G>T (CYP2B6*6 and CYP2B6*9). In conclusion, a novel CYP2B6*16 allele causing less expression of the corresponding enzyme was identified and found to influence the metabolism of efavirenz in vivo, a finding that is of potential impact for anti-HIV therapy in black populations.
Pharmacogenetics and Genomics 04/2006; 16(3):191-8. · 3.48 Impact Factor
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ABSTRACT: Our objective was to prospectively study the impact of CYP2C9 polymorphism (*2 and *3) on the risk of overanticoagulation during the induction phase of warfarin therapy.
Blood samples for genotyping were collected from 219 patients requiring warfarin therapy, and clinical data were prospectively collected during the first 3 weeks of medication. Patients were divided into 3 groups according to CYP2C9 genotype, as follows: *1 (homozygous), *2 (*1/*2 and *2/*2), and *3 (any genotype containing the *3 allele).
During the first week of treatment, the relative risk of achieving at least 1 international normalized ratio (INR) value above the therapeutic interval (2-3) was 2.8 (95% confidence interval, 1.2-6.7) and 6.1 (2.7-13.6) in the *2 and *3 groups, respectively (with *1 used as control). During the second week, the corresponding values were 2.1 (1.2-3.7) and 3.5 (2.1-5.8), respectively. By the third week, the genetic impact was no longer evident, presumably as a result of successful dose individualization. Increased INR levels (compared with the *1 group) were already demonstrated in the *2 group on the fourth treatment day.
The CYP2C9*2 and *3 single-nucleotide polymorphisms significantly increase the risk of overanticoagulation during the first 2 weeks of warfarin treatment, with increased INR levels evident after only 4 days' treatment in *2 carriers. Our prospective data are consistent with results from previous retrospective studies and indicate that CYP2C9 genotyping may be a means of improving safety during warfarin induction.
Clinical Pharmacology & Therapeutics 12/2005; 78(5):540-50. · 6.04 Impact Factor
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ABSTRACT: To test the hypotheses that (1) CYP2D6 genotype is associated with pharmacokinetics of ophthalmic timolol and (2) variation in genotypes of ADRB1 (beta(1)-adrenoceptor) and GNAS1 (alpha-subunit of G-protein) modulate heart rate (HR), and systolic (SAP) and diastolic (DAP) arterial pressure responses to timolol.
Nineteen glaucoma patients and eighteen healthy volunteers were treated with 0.5% aqueous and 0.1% hydrogel formulations of ophthalmic timolol using a randomised cross-over design. The participants conducted head-up tilt and maximum exercise test at four visits. Plasma concentration of timolol was measured twice for glaucoma patients and ten times for healthy volunteers on each visit. Also, the genotypes for CYP2D6, ADRB1 and GNAS1 were determined.
Among healthy volunteers using aqueous timolol, poor metabolisers (PMs, n=2) of CYP2D6 had higher maximum plasma concentrations (C(max), values 2.63 and 2.94 ng/ml), longer elimination half-lives ( T(1/2), 5.49 and 6.75 h), and higher area-under-curve (AUC, 19.54 and 23.25 ng.h/ml) than intermediate [IMs, n=6, mean+/-SD 1.73+/-0.59 ng/ml (not significant), 3.30+/-0.48 h, 11.32+/-3.72 ng.h/ml], extensive (EMs, n=8, 1.60+/-0.72 ng/ml, 3.24+/-1.24 h, 8.52+/-6.12 ng.h/ml) and ultra-rapid (UMs, n=2, values 1.23 and 1.67 ng/ml, 2.22 and 2.52 h, 6.16 and 6.94 ng.h/ml) metabolisers. The IMs, EMs and UMs did not differ from each other for any of the kinetic variables. Also, the elevation of HR from rest to maximum level tended to differ between PMs and IMs, and between PMs and UMs. The pharmacokinetics and pharmacodynamics between the CYP2D6 groups did not differ with statistical significance when hydrogel timolol was used. Upon head-up tilt, the Ser49 homozygotes (n=26) had higher SAP (P=0.03) and DAP (P<0.01) than the Gly carriers (n=11). The change in DAP from rest to maximum during exercise was lower (P<0.01) in subjects with CC alleles of GNAS1 (n=13) than those with at least one T allele (n=24).
The CYP2D6 poor metabolisers may be more prone to systemic adverse events with aqueous timolol than extensive metabolisers. Since CYP2D6 genotyping is not routine clinical practice, using 0.1% timolol hydrogel instead of 0.5% aqueous preparation will increase patient safety.
European Journal of Clinical Pharmacology 12/2005; 61(11):811-9. · 2.85 Impact Factor
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ABSTRACT: The aim of this study was to quantify the mRNA expression of three cytochromes P450 (CYP) and P-glycoprotein (P-gp) in the human gastrointestinal (GI) tract.
Biopsies were obtained from gastric, duodenal, colonic and rectal mucosa during routine gastro-colonoscopy in 27 patients. The biopsies were snap-frozen in liquid nitrogen. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was used for the quantitative analyses of mRNA expressed by the CYP2E1, CYP3A4 and CYP3A5 genes, and the MDR1 gene coding for P-gp protein. The mRNA expression of b-actin was used as an internal standard for comparisons between samples.
All CYP genes were expressed at all locations throughout the GI tract, although all showed substantial interindividual variation. CYP2E1 had the highest expression at all locations (P < 0.05 to P < 0.0001), except in the right colon. CYP3A4 and CYP3A5 had their highest mRNA expression in the duodenum (P < 0.001 and P < 0.000 001, respectively) and CYP2E1 in the stomach (P < 0.01). MDR1 mRNA concentrations increased along the GI tract with the highest expression being in the left colon (P < 0.000001).
Multiple sampling within the same individual enabled us to study the intraindividual variation in expression of CYP and MDR1 genes along the GI tract. We find that CYP2E1 mRNA expression is higher than that of the other CYPs. CYP3A expression is highest in the duodenum and that of MDR1 increases from stomach and duodenum to colon.
British Journal of Clinical Pharmacology 08/2005; 60(1):54-60. · 2.96 Impact Factor
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ABSTRACT: Our objective was to study in vivo the role of CYP2C and CYP3A4 in the disposition of 3-keto-desogestrel after administration of desogestrel, by using the selective inhibitors fluconazole (CYP2C) and itraconazole (CYP3A4).
This study had a three-way crossover design and included 12 healthy females, the data from 11 of whom were analyzed. In the first (control) phase all subjects received a single 150 microg oral dose of desogestrel alone. In the second and third phases subjects received a 4 day pretreatment with either 200 mg fluconazole or 200 mg itraconazole once daily in a randomized balanced order. Desogestrel was given 1 h after the last dose of the CYP inhibitor. Plasma 3-keto-desogestrel concentrations were determined for up to 72 h post dose.
Pretreatment with itraconazole for 4 days significantly increased the area under the plasma concentration-time curve (AUC) of 3-keto-desogestrel by 72.4% (95% confidence interval on the difference 12%, 133%; P = 0.024) compared with the control phase, whereas fluconazole pretreatment had no significant effect (95% CI on the difference -42%, 34%). Neither enzyme inhibitor affected significantly the maximum concentration (95% CI on the difference 14%, 124% for itraconazole and -23%, 40% for fluconazole) or elimination half-life (95% CI on the difference -42%, 120% for itraconazole and -24%, 61% for fluconazole) of 3-keto-desogestrel.
According to the present study, the biotransformation of desogestrel to 3-keto-desogestrel did not appear to be mediated by CYP2C9 and CYP2C19 as suggested earlier. However, the further metabolism of 3-keto-desogestrel seems to be catalyzed by CYP3A4.
British Journal of Clinical Pharmacology 08/2005; 60(1):69-75. · 2.96 Impact Factor
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Duodecim; lääketieteellinen aikakauskirja 02/2005; 121(2):177-80.
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ABSTRACT: The aim of this study was to (a) quantify the gene expression of some cytochromes P(450) (CYP), especially CYP3A4, in serial biopsies from liver grafts the first year after orthoptic liver transplantation (OLT) and (b) study the relationship between hepatic CYP3A4 gene expression and plasma levels of cyclosporine and tacrolimus.
Liver tissue was obtained from surplus material of routine liver biopsies performed in 20 patients during the first year after OLT. Real-time reverse-transcription polymerase chain reaction was used for quantitative analyses of mRNA specific for CYP3A4, CYP3A5, CYP2E1 and CYP1A2 cytochromes as well as P-glycoprotein (P-gp). The gene expression of beta-actin was used as an internal standard for comparisons between samples.
The median value of the mRNA for all cytochromes, but not for P-gp, was found to increase significantly over time. The gene expression of CYP3A5, CYP2E1 and CYP1A2 was higher than that of CYP3A4. The gene expression of CYP3A4 was related to the plasma concentration of cyclosporine and tacrolimus, i.e. low mRNA concentrations corresponded to high serum concentration levels and vice versa. The serum concentration of bilirubin or the prothrombin index did not correlate with the gene expression level of the cytochromes.
The hepatic mRNA expression of CYP3A4 and the other investigated cytochromes increased during the first year after OLT. This was not the case with P-gp. Low CYP3A4 gene expression was related to high plasma levels of cyclosporine and tacrolimus and vice versa.
European Journal of Clinical Pharmacology 09/2004; 60(6):413-20. · 2.85 Impact Factor
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ABSTRACT: ObjectiveThe aim of this study was to (a) quantify the gene expression of some cytochromes
P450 (CYP), especially CYP3A4, in serial biopsies from liver grafts the first year after orthoptic liver transplantation (OLT) and (b) study the relationship between hepatic CYP3A4 gene expression and plasma levels of cyclosporine and tacrolimus.MethodsLiver tissue was obtained from surplus material of routine liver biopsies performed in 20 patients during the first year after OLT. Real-time reverse-transcription polymerase chain reaction was used for quantitative analyses of mRNA specific for CYP3A4, CYP3A5, CYP2E1 and CYP1A2 cytochromes as well as P-glycoprotein (P-gp). The gene expression of -actin was used as an internal standard for comparisons between samples.ResultsThe median value of the mRNA for all cytochromes, but not for P-gp, was found to increase significantly over time. The gene expression of CYP3A5, CYP2E1 and CYP1A2 was higher than that of CYP3A4. The gene expression of CYP3A4 was related to the plasma concentration of cyclosporine and tacrolimus, i.e. low mRNA concentrations corresponded to high serum concentration levels and vice versa. The serum concentration of bilirubin or the prothrombin index did not correlate with the gene expression level of the cytochromes.ConclusionThe hepatic mRNA expression of CYP3A4 and the other investigated cytochromes increased during the first year after OLT. This was not the case with P-gp. Low CYP3A4 gene expression was related to high plasma levels of cyclosporine and tacrolimus and vice versa.
European Journal of Clinical Pharmacology 08/2004; 60(6):413-420. · 2.85 Impact Factor
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ABSTRACT: Recent studies have revealed that genetic polymorphisms of cytochrome P(450) 2D6 (CYP2D6) are among the factors that determine the interindividual differences in the metabolism and response to antidepressants. We investigated the relationship between persistent mood disorders and the duplication of the CYP2D6 gene, which encodes an enzyme with increased activity.
We screened the prevalence of the CYP2D6 genotypes in 108 patients with persistent mood disorders using long polymerase chain reaction (PCR) and the real-time PCR methods. Clinical correlates with the genotypes were also analyzed.
Among the 108 patients, 81 had failed to respond to antidepressants shown to be metabolized by CYP2D6. Of those 81, 8 had a CYP2D6 gene duplication (9.9%, 95% confidence interval 3.4-16.4%) which was higher than the 0.8-1.0% incidence previously observed in healthy Nordic Caucasians. The worst week scores of the Hamilton Depression Rating Scale were higher in the patients with the duplication compared with those without the duplication ( P=0.026, student's t-test).
These results suggest that the CYP2D6 gene duplication is a possible factor that influences the development of persistence in patients with mood disorders probably by ultrarapid drug metabolism.
European Journal of Clinical Pharmacology 02/2004; 59(11):803-7. · 2.85 Impact Factor
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ABSTRACT: Cytochromes P450 (CYP) 2C8 and 2C9 are polymorphic enzymes responsible for the biosynthesis of vasoactive substances from arachidonic acid including endothelium-derived hyperpolarizing factor. Inter-individual differences in the action of these substances might be important in the pathogenesis of cardiovascular diseases such as acute myocardial infarction (AMI) and hypertension. This study describes the relationship between genetic variants of CYP2C8 and CYP2C9, and morbidity in myocardial infarction in a large Swedish patient material. The study included 1172 AMI patients and 1503 control subjects (matched by age, sex and residential area) who participated in the Stockholm Heart Epidemiology Program (SHEEP). Genotyping was performed by allelic discrimination using a 5'-nuclease assay for the CYP2C8 and CYP2C9 variants. To estimate associations to AMI risks, odds ratios (OR) with 95% confidence intervals (CI) were calculated. The frequencies of CYP2C8*1, 2C8*3, 2C9*1, 2C9*2 and 2C9*3 variants in the control group were 0.91, 0.095, 0.83, 0.11 and 0.065, respectively. The risk of AMI in the female individuals carrying the *2 or *3 variant alleles of CYP2C9 and that of all individuals carrying the *3 variant of CYP2C8 was higher [OR (95% CI): 1.3 (1.0-1.9), P = 0.09; 1.5 (1.0-2.2), P = 0.06 and 1.2 (1.0-1.5), P = 0.07, respectively] compared to the groups with CYP2C8*1 and CYP2C9*1. Possession of rare genetic variants of the CYP2C8 and CYP2C9 genes in females is associated with a modest increase in risk of AMI. This might be related to genetic differences in the formation of endogenous vasoregulating eicosanoids.
Pharmacogenetics 01/2004; 13(12):715-20.
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ABSTRACT: Our objective was to study the effect of hormone replacement therapy and a combination oral contraceptive on the cytochrome P450 (CYP) 2B6 activity with bupropion (INN, amfebutamone) hydroxylation used as a probe reaction.
This was a 3-way crossover study with 12 healthy female volunteers. The first phase was a control phase, in which all subjects received a single 150-mg dose of bupropion (sustained release) without pretreatment. In the second and third phases, in randomized balanced crossover order, subjects received a 10-day pretreatment with either hormone replacement therapy, containing 2 mg estradiol valerate and 250 microg levonorgestrel, or an oral contraceptive, containing 30 microg ethinyl estradiol (INN, ethinylestradiol) and 150 microg desogestrel, and the bupropion dose was given 1 hour after the last hormone dose. The bupropion, hydroxybupropion, and hydrobupropion plasma concentrations were determined for up to 72 hours.
The 10-day hormone replacement therapy pretreatment reduced the hydroxybupropion/bupropion area under the plasma concentration-time curve (AUC) ratio by 49% (P <.001; 95% confidence interval [CI], -58% to -40%) as a result of a marked 47% decrease (P <.001; 95% CI, -54% to -41%) in the AUC of hydroxybupropion. Moreover, the AUC of hydrobupropion was significantly (64%; P =.003; 95% CI, 22% to 106%) increased. The AUC of hydroxybupropion was also reduced after the oral contraceptive treatment but to a lesser extent (-31%; P <.001; 95% CI, -37% to -26%). However, the hydroxybupropion/bupropion AUC ratio was not significantly affected.
Hormone replacement therapy markedly inhibited the CYP2B6-catalyzed hydroxylation of bupropion, whereas a combination oral contraceptive had only a modest effect on CYP2B6 activity. Patients receiving hormone replacement therapy or oral contraceptives may need dose adjustment when treated with drugs metabolized by CYP2B6.
Clinical Pharmacology & Therapeutics 10/2003; 74(4):326-33. · 6.04 Impact Factor
