Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

P-glycoprotein (PGP) is a polymorphic efflux transporter located on the blood brain barrier that potentially affects the penetration of atypical antipsychotics into the central nervous system. Increased antipsychotic penetration to the primary site of activity may result in greater symptom improvement or the occurrence of side effects. This investigation examined the relationship between three common PGP polymorphisms (C1236T, G2677TA, and C3435T) and response to 6 weeks of open-label olanzapine treatment in patients with schizophrenia. Individuals with a PGP T allele at any of these polymorphisms would be expected to have greater antipsychotic penetration through the blood brain barrier, due to lower PGP activity. Forty-one patients were included in this reanalysis. For subjects in the 3435T allele carrier group, the plasma olanzapine level alone was positively associated with percent change in Brief Psychiatric Rating Scale score (p = 0.02). This relationship was not seen for the 3435CC group (p = 0.583). A similar trend was observed for negative symptom reduction, olanzapine plasma concentration, and the 3435T allele (p = 0.06), but this relationship did not meet statistical significance. There was no relationship between the PGP genotypes and changes in weight over the course of this 6 week study. The analysis using C1236T or G2677AT genotypes gave similar results, due to linkage of these polymorphisms.PGP polymorphisms may affect the penetration of olanzapine into the central nervous system as seen by a relationship between the 3435T allele, olanzapine plasma levels, and reduction in the positive symptoms of schizophrenia. This may stem from greater olanzapine central nervous system latency due to the presence of the 3435T allele and reduced PGP activity. The PGP C3435T genotype may help to determine positive symptom reduction from olanzapine clinically, but these findings should be replicated in a larger sample of subjects.
Ther Drug Monit 2006 Oct
PMID:The relationship between P-glycoprotein (PGP) polymorphisms and response to olanzapine treatment in schizophrenia. 1703 83

Inherited differences in xenobiotic transport and metabolism may play an important role in the development of adult acute myeloid leukemia (AML) and response to the chemotherapy. An ATP-binding cassette (ABC) family transporter P-glycoprotein (P-gp or ABCB1), encoded by ABCB1 (MDR1) gene, is involved in the protection against xenobiotics and multi-drug resistance. The aim of this study was to investigate the potential involvement of the ABCB1 gene exon 26 3435C>T single nucleotide polymorphism (SNP) in the genetic susceptibility to AML and regulation of P-gp expression and activity in AML cells. A total of 180 adult AML patients and 180 sex-matched controls were genotyped using PCR-RFLP method. Moreover, in 40 AML patients ABCB1 gene expression was studied by real-time RT-PCR and P-gp expression and activity were assessed by flow cytometry assays. The prevalence of 3435C>T ABCB1 polymorphism was similar in patient and control cohorts (P = 0.16). Furthermore, the carriers of different ABCB1 genotypes did not differ significantly according to ABCB1 gene expression (P = 0.99), P-gp expression (P = 0.42) and P-gp activity (P = 0.83) in leukemic cells. The authors conclude that isolated 3435C>T ABCB1 SNP is not a major factor of the genetic susceptibility to adult AML, and that genotyping of this polymorphism does not allow predicting P-gp expression or activity in AML cells.
Ther Drug Monit 2006 Oct
PMID:No influence of 3435C>T ABCB1 (MDR1) gene polymorphism on risk of adult acute myeloid leukemia and P-glycoprotein expression in blast cells. 1703 91

A recent in vitro study has shown that paroxetine is a substrate of P-glycoprotein. However, there was no in vivo information indicating the involvement of P-glycoprotein on the pharmacokinetics of paroxetine. The aim of this study was to examine the effects of itraconazole, a P-glycoprotein inhibitor, on the pharmacokinetics of paroxetine. Two 6 day courses of either 200 mg itraconazole daily or placebo with at least a 4 week washout period were conducted. Thirteen volunteers took a single oral 20 mg dose of paroxetine on day 6 of both courses. Plasma concentrations of paroxetine were monitored up to 48 hours after the dosing. Compared with placebo, itraconazole treatment significantly increased the peak plasma concentration (Cmax) of paroxetine by 1.3 fold (6.7 +/- 2.5 versus 9.0 +/- 3.3 ng/mL, P < 0.05) and the area under the plasma concentration-time curve from zero to 48 hours [AUC (0-48)] of paroxetine by 1.5 fold (137 +/- 73 versus 199 +/- 91 ng*h/mL, P < 0.01). Although elimination half-life differed significantly (16.1 +/- 3.4 versus 18.8 +/- 5.9 hours, P < 0.05), the alteration was small (1.1 fold). The present study demonstrated that the bioavailability of paroxetine was increased by itraconazole, suggesting a possible involvement of P-glycoprotein in the pharmacokinetics of paroxetine.
Ther Drug Monit 2007 Feb
PMID:Effect of itraconazole on pharmacokinetics of paroxetine: the role of gut transporters. 1730 49

Cytochrome P450 (CYP) 3A4 is the most abundant enzyme of CYPs in the liver and gut that metabolizes approximately 50% currently available drugs. A number of important drugs have been identified as substrates, inducers, and/or inhibitors of CYP3A4. The substrates of CYP3A4 considerably overlap with those of P-glycoprotein. Both CYP3A4 and P-glycoprotein are subject to inhibition and induction by a number of factors. Mechanism-based inhibition of CYP3A4 is characterized by NADPH-, time-, and concentration-dependent enzyme inactivation occurring when some xenobiotics or drugs are converted by CYPs to reactive metabolites. Such an inhibition of CYP3A4 is caused by chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. To date, the identified clinically important mechanism-based CYP3A4 inhibitors mainly include macrolide antibiotics (eg, clarithromycin and erythromycin), anti-HIV agents (eg, ritonavir and delavirdine), antidepressants (eg, fluoxetine and fluvoxamine), calcium channel blockers (eg, verapamil and diltiazem), steroids and their modulators (eg, gestodene and mifepristone), and several herbal and dietary components. The inactivation of CYP3A4 by drugs often causes unfavorable and long-lasting drug-drug interactions and probably fatal toxicity, depending on many factors associated with the enzyme, drugs, and the patients. Clinicians are encouraged to have a sound knowledge of drug-induced, mechanism-based CYP3A4 inhibition; take proper cautions, and perform close monitoring for possible drug interactions when using drugs that are mechanism-based CYP3A4 inhibitors. To minimize drug-drug interactions involving mechanism-based CYP3A4 inhibition, it is necessary to choose safe drug combination regimens, adjust drug dosages appropriately, and conduct therapeutic drug monitoring for drugs with narrow therapeutic indices.
Ther Drug Monit 2007 Dec
PMID:Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. 1804 68

In two separate pharmacokinetic studies, the drug interaction between immunosuppressive agents was examined in a total of 12 cardiac transplant recipients by conversion of the concomitant immunosuppressant. In six patients under continuous tacrolimus therapy, the concomitant drug azathioprine was converted to everolimus (PK-TAC study). No significant effect on tacrolimus pharmacokinetic parameters was observed. In the second study in which the patients were converted from cyclosporine to tacrolimus under continuous everolimus therapy (PK-EVL study), a significant decrease in everolimus predose concentration (from 4.2 to 2.3 microg/L), maximum concentration (from 9.1 to 5.9 microg/L), and area under the concentration time curve (mean values decreased from 64.2 to 33.7 microg*h/L) was found, indicating a lower everolimus exposure. A pharmacokinetic interaction between cyclosporine and everolimus has been described previously for healthy volunteers after single-dose application and presumably originates from a comparatively greater inhibition of hepatic CYP3A4 or P-glycoprotein efflux transporter with a low-dose cyclosporine regimen. Our results confirm this interaction under clinical conditions and suggest close drug monitoring when converting the calcineurin inhibitor under concomitant mammalian target of rapamycin-inhibitor therapy.
Ther Drug Monit 2008 Feb
PMID:Everolimus exposure in cardiac transplant recipients is influenced by concomitant calcineurin inhibitor. 1822 73

Herbal supplements can affect concentrations of therapeutic drugs measured in biological fluids by different mechanisms. Herbal products can either directly interfere with the methodology used in the measurement of drugs or indirectly interfere by altering the pharmacokinetics of coadministered drugs. The active components of Chan Su, Lu-Shen-Wan, Dan Shen, Asian and Siberian ginseng, oleander containing supplements, and Ashwagandha interfere with digoxin measurements by immunoassays, especially the polyclonal antibody-based immunoassays. Herbal supplements are sometimes contaminated with Western drugs causing drug toxicity. A therapeutic drug monitoring (TDM) service is very helpful for diagnosis of drug toxicity in such patients. Herbal products such as St. John's wort, a popular herbal antidepressant, increase the clearance of certain drugs either by increasing the activity of liver or intestinal cytochrome P-450 mixed-function oxidase or through modulation of the P-glycoprotein efflux pump. Significantly reduced concentrations of various therapeutic drugs such as digoxin, theophylline, cyclosporine, tacrolimus, tricyclic antidepressants, warfarin, and protease inhibitors can be observed due to interaction of these drugs with St. John's wort, causing treatment failure. On the other hand, a few drugs such as carbamazepine, mycophenolic acid, and procainamide do not show any interaction with St. John's wort. Understanding the effect of herbal products on TDM methodologies and identification of interactions between herbal products and drugs by TDM are very important clinically.
Ther Drug Monit 2008 Apr
PMID:Herbal supplements and therapeutic drug monitoring: focus on digoxin immunoassays and interactions with St. John's wort. 1836 83

An open-label, clinical pilot study was performed to study the effect of cyclosporine A (CsA) on single-dose pharmacokinetics of itraconazole in patients with a hematologic malignancy. Patients (n = 10), admitted for allogeneic stem cell transplantation, received a single dose of 200 mg itraconazole in a 1-hour intravenous infusion during their treatment period before initiation of CsA. This was repeated during the period that CsA was administered and a steady-state concentration of CsA was achieved (trough whole blood level 200-400 ng/mL). After both administrations of itraconazole, serum pharmacokinetics of itraconazole and hydroxy (OH) itraconazole were determined during 24 hours. The results were compared with each patient acting as his or her own control. Exposure to itraconazole, as measured by the AUC[0-24h], was not significantly altered when combined with CsA. Large interindividual variations were observed in area under the concentration curve values among patients. In contrast, exposure to OH-itraconazole was significantly increased when itraconazole was coadministered with CsA (median increase of AUC[0-24h] 49%) with significant prolongation of T(max) and T1/2 (median increase of T(max) 37% and T1/2 176%). These differences may be the result of variability in affinity of itraconazole, OH-itraconazole, and CsA for the cytochrome P450 3A4 metabolic system and the occurrence of P-glycoprotein polymorphisms. In conclusion, exposure to OH-itraconazole, but not to itraconazole, is increased when itraconazole is coadministered with CsA. Although the interaction profile of itraconazole and CsA remains complex, these findings may be of importance in patients in whom monitoring of itraconazole serum levels is warranted, for example, in those with life-threatening fungal infections or in those who receive concurrent cytochrome inducers or inhibitors.
Ther Drug Monit 2008 Jun
PMID:Effects of cyclosporine a on single-dose pharmacokinetics of intravenous itraconazole in patients with hematologic malignancies. 1852 Jun 1

Mycophenolic acid (MPA) is mainly glucuronized by uridine diphosphate-glucuronosyltransferases (UGTs) into the phenolic MPA glucuronide (MPAG). MPAG is excreted by transporters such as organic anion-transporting polypeptide (gene SLCO), multidrug resistance protein 2 (gene ABCC2), breast cancer resistance protein (BCRP, gene ABCG2) or P-glycoprotein (gene ABCB1). This study investigated the association of UGTs, SLCOs, ABCB1, ABCC2, and ABCG2 polymorphisms with MPAG pharmacokinetics in 80 Japanese renal transplant recipients. Eighty recipients were given repeated doses of combination immunosuppressive therapy consisting of mycophenolate mofetil and tacrolimus every 12 hours at a designated time (0900 and 2100). On day 28, after renal transplantation, plasma concentrations of MPA and MPAG were measured by high-performance liquid chromatography. There were no significant differences in the area under the plasma concentration-time curve (AUC) ratio of MPAG/MPA between UGT1A1, UGT1A6, UGT1A7, UGT1A8, and UGT1A9 I399C/T genotypes. On the other hand, the median dose-adjusted AUC0-12 of MPAG in SLCO1B1 1a/1a+1a/1b+1b+1b (n = 53) and 1a/*15 + 1b/*15+*15/*15 (n = 27) were 1549 and 1134 mg.h L g, respectively (P = 0.03004 in multivariate analysis). The median dose-adjusted AUC0-12 of MPAG in SLCO1B3 334T/T+T/G (699G/G+G/A, n = 46) and 334G/G (699A/A, n = 34) was 1191 and 1580 mg.h L g, respectively (P = 0.02792 in multivariate analysis). There were no significant differences in the dose-adjusted AUC0-12 of MPAG between the ABCB1 C3435T and ABCC2 C-24T genotypes. However, the dose-adjusted AUC0-12 of MPAG was significantly lower in recipients with ABCG2 421C/A+A/A (n = 44) than in those with C/C (n = 36) (P = 0.0295). In conclusion, our findings showed that MPAG pharmacokinetics were significantly influenced by SLCO1B1 and SLCO1B3 polymorphisms and not by UGT polymorphisms. BCRP rather than multidrug resistance protein 2 seems to be the transporter associated with biliary excretion of MPAG.
Ther Drug Monit 2008 Oct
PMID:Influence of drug transporters and UGT polymorphisms on pharmacokinetics of phenolic glucuronide metabolite of mycophenolic acid in Japanese renal transplant recipients. 1869 35

Risperidone is metabolized to its active metabolite, 9-hydroxyrisperidone, mainly by the cytochrome P450 enzymes CYP2D6 and 3A4. Its antipsychotic effect is assumed to be related to the active moiety, that is, the sum of risperidone and 9-hydroxyrisperidone. Both risperidone and 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp), a transport protein involved in drug absorption, distribution, and elimination. The aim of the present study was to evaluate the influence of polymorphisms in genes encoding CYP3A5 and P-gp (ABCB1) on the steady-state plasma levels of risperidone, 9-hydroxyrisperidone, and the active moiety, taking CYP2D6 genotype status into account. Forty-six white patients with schizophrenia treated with risperidone (1-10 mg/d) in monotherapy for 4-6 weeks were genotyped, and their plasma concentrations of risperidone and 9-hydroxyrisperidone were measured. Dose-corrected plasma concentrations (C/D) of risperidone, 9-hydroxyrisperidone, and active moiety showed up to 68-, 9-, and 10-fold interindividual variation, respectively. Six patients carried 1 CYP3A5*1 allele and therefore were likely to express the CYP3A5 enzyme. The CYP3A5 genotype did not influence risperidone, 9-hydroxyrisperidone, or active moiety C/Ds. The CYP2D6 genotype in these 46 patients was again associated with risperidone C/D (P = 0.001) but not with 9-hydroxyrisperidone C/D or active moiety C/D, as previously shown by our group in 37 of these patients. Patients homozygous for the ABCB1 3435T/2677T/1236T haplotype had significantly lower C/Ds of 9-hydroxyrisperidone (P = 0.026) and active moiety (P = 0.028) than patients carrying other ABCB1 genotypes. In conclusion, our results confirmed the significant effect of CYP2D6 genotype on the steady-state plasma levels of risperidone and showed that ABCB1 polymorphisms have a moderate effect on those of 9-hydroxyrisperidone and the active moiety.
Ther Drug Monit 2008 Oct
PMID:ABCB1 polymorphisms influence steady-state plasma levels of 9-hydroxyrisperidone and risperidone active moiety. 1870 91

A case of a 46-year-old woman with schizophrenia who was treated with risperidone and followed up for 1 year is reported. She was genotyped as a CYP2D6 poor metabolizer (PM): CYP2D6-4*/*6, which was confirmed by a dextromethorphan (DM) test (metabolic ratio = 5.8). Genotypes of ABCB1 (MDR1) were 2677TT and 3435TT. Because risperidone is CYP2D6 and P-glycoprotein substrate, the patient might have been expected to accumulate risperidone and suffer from significant side effects. However, the patient tolerated the drug extremely well. Plasma concentration of risperidone was 73.2 nmol/L and of 9-OH-risperidone was below the limit of quantitation (6.1 nmol/L). Target range of risperidone plus 9-hydroxyrisperidone is 50-150 nmol/L. During the follow-up, patient was continuously taking 3 mg/day of risperidone. Plasma levels of risperidone and 9-OH-risperidone were 70.2 and 18.1 nmol/L, respectively. We repeated a DM test, metabolic ratio was 3.6, thus confirming that the patient remained a PM. Psychopathology was assessed with Positive and Negative Syndrome Scale, and stable remission of illness was achieved over the stated period. No adverse effects were observed or reported by the patient. We conclude that PM phenotype for CYP2D6 does not necessarily have clinical significance in regard to risperidone treatment. DM and risperidone are both CYP2D6 and P-glycoprotein substrates and significant interactions might occur with both drugs, in parallel with the possible impact of ABCB1 and CYP2D6 polymorphic gene variants.
Ther Drug Monit 2008 Dec
PMID:Clinical significance of a CYP2D6 poor metabolizer--a patient with schizophrenia on risperidone treatment. 1880 96


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