Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Tacrolimus hydrate, a potent immunosuppressant produced by Streptomyces tsukubaensis, was examined for its effect on epirubicin activity in multidrug-resistant P388 leukemia (P388/R) cells overexpressing P-glycoprotein and the parent (P388/S) cells. In the absence of modulator, the 50% inhibitory concentration for epirubicin after 48-h incubation, determined using a microculture tetrazolium assay, was 0.8 microgram/ml in P388/R cells and 0.009 microgram/ml in P388/S cells. P388/R cells demonstrated a 90-fold reduction in sensitivity to epirubicin. Tacrolimus hydrate (1 and 10 microM) markedly enhanced epirubicin cytotoxicity by 4.2- and 26.7-fold for P388/R cells. A significant increase in LDH release from cells by tacrolimus hydrate was also observed in P388/R cells treated with epirubicin. Tacrolimus hydrate had a marked effect on epirubicin-induced G2/M blockade in the resistant cells. Both tacrolimus hydrate and cyclosporin A dramatically increased the accumulation of epirubicin by the resistant cells, while these compounds had no effect on epirubicin accumulation in the parent cells. Thus, tacrolimus hydrate is able to down-modulate P-glycoprotein-associated resistance through inhibition of P-glycoprotein function, suggesting that the drug may be a candidate for killing drug-resistant tumor cells.
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PMID:Reversal of multidrug resistance by tacrolimus hydrate. 912 Dec 20

Tacrolimus is a marketed immunosuppressant used in liver and kidney transplantation. It is subject to extensive metabolism by CYP3A4 and is a substrate for P-glycoprotein-mediated transport. A pharmacokinetic interaction with rifampin, an antituberculosis agent and potent inducer of CYP3A4 and P-glycoprotein, and tacrolimus was evaluated in six healthy male volunteers. Tacrolimus was administered at doses of 0.1 mg/kg orally and 0.025 mg/kg/4 hours intravenously. The pharmacokinetics of tacrolimus were obtained from serial blood samples collected over 96 hours, after single oral and intravenous administration prior to and during an 18-day concomitant rifampin dosing phase. Coadministration of rifampin significantly increased tacrolimus clearance (36.0 +/- 8.1 ml/hr/kg vs. 52.8 +/- 9.6 ml/hr/kg; p = 0.03) and decreased tacrolimus bioavailability (14.4% +/- 5.7% vs. 7.0% +/- 2.7%; p = 0.03). Rifampin appears to induce both intestinal and hepatic metabolism of tacrolimus, most likely through induction of CYP3A and P-glycoprotein in the liver and small bowel.
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PMID:Effects of rifampin on tacrolimus pharmacokinetics in healthy volunteers. 998 5

Tacrolimus is an immunosuppressant used to prevent rejection of transplanted organs. It is metabolized in both the gut and the liver by the cytochrome P450 (CYP) 3A4 enzyme system and is a substrate for the P-glycoprotein (P-gp) drug efflux pump. As CYP3A4 enzymes and P-gp are present at differing concentrations throughout the gastrointestinal tract, the bioavailability of tacrolimus may be influenced by changes in gastrointestinal transit time in addition to changes in hepatic metabolism. We report the case of a pediatric renal transplant patient who experienced a three-fold increase in serum tacrolimus concentrations during an episode of gastroenteritis with chronic diarrhea.
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PMID:Increased tacrolimus levels in a pediatric renal transplant patient attributed to chronic diarrhea. 1073 Oct 62

The present study examines whether resistance to Cyclosporin A (CyA) and Tacrolimus (FK506) develops in T cells from individual patients and the role of P-glycoprotein 170 (P-gp) in mediating drug resistance. IC50s were established for CyA and FK506 in cell cultures from 46 renal allograft recipients. P-gp expression and functional activity were determined by flow cytometry. Mean ID50 for CyA was 29 microg/li (range 2.5-100) and for FK506 1.2 microg/li (range 0.085-5.5). The sensitivities to the two drugs were correlated (P = 0.0001). There was variation in the ratio of the ID50s depending on the drug used for treatment (P = 0.02). There was no difference in P-gp expression and functional activity in patients with sensitive or resistant cells. The data indicate an association between the sensitivities to CyA and FK506 and evidence of selective resistance to whichever drug was used. P-gp drug transport does not explain this variation.
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PMID:Constitutive and acquired resistance to calcineurin inhibitors in renal transplantation: role of P-glycoprotein-170. 1095 80

Tacrolimus is a drug for which therapeutic drug monitoring is recommended. The existence of a wide variety of potential drug interactions further supports the current strategy of measuring whole blood tacrolimus concentrations in transplanted patients. Cytochrome P450 (CYP)3A, the major phase I metabolising enzyme in humans, and the multi-drug efflux pump, P-glycoprotein, are present at high levels in the villus tip of enterocytes in the gastrointestinal tract. Oral bioavailability of tacrolimus can be increased by concomitant administration of inhibitors of either CYP3A or P-glycoprotein. CYP activity in the liver also influences tacrolimus concentrations. As a result, several drugs that are frequently being used in transplantation, such as corticosteroids and antifungal agents, will affect tacrolimus concentrations. Knowledge of such drug interactions is extremely important, as they may lead to clinically important under- or overexposure to tacrolimus, with acute rejection episodes or serious toxicity as a result.
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PMID:Drug interactions with tacrolimus. 1216 66

Tacrolimus is a substrate for P-glycoprotein (P-gp) and cytochrome (CYP) P4503A. P-gp is encoded by the multiple drug resistance gene MDR1 and CYP3A is the major enzyme responsible for tacrolimus metabolism. Both MDR1 and CYP3A5 genes have multiple single nucleotide polymorphisms. The objective of this study was to evaluate whether the MDR1 exon21 and exon26 polymorphisms and the CYP3A5 polymorphism are associated with tacrolimus disposition in pediatric heart transplant patients. At 3, 6 and 12 months post transplantation, a significant difference in tacrolimus blood level per dose/kg/day was found between the CYP3A5 *1/*3 (CYP3A5 expressor) vs. *3/*3 (nonexpressor) genotypes with the *1/*3 patients requiring a larger tacrolimus dose to maintain the same blood concentration. There were no significant differences in tacrolimus blood level per dose/kg/day between MDR1 exon21 G2677T and exon 26 C3435T at 3 months, but both were found to have a significant association with tacrolimus blood level per dose/kg/day at 6 and 12 months. We conclude that specific genotypes of MDR1 and CYP3A5 in pediatric heart transplant patients require larger tacrolimus doses to maintain their tacrolimus blood concentration, and that this information could be used prospectively to manage patient's immunosuppressive therapy.
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PMID:Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms. 1269 72

The immunosuppressive drug tacrolimus, whose pharmacokinetic characteristics display large interindividual variations, is a substrate for P-glycoprotein (P-gp), the product of the multidrug resistance-1 (MDR1) gene. Some of the single nucleotide polymorphisms (SNP) of MDR1 reported correlated with the in vivo activity of P-gp. Because P-gp is known to control tacrolimus intestinal absorption, it was postulated that these polymorphisms are associated with tacrolimus pharmacokinetic variations in renal transplant recipients. The objective of this study was to evaluate in a retrospective study of 81 renal transplant recipients the effect on tacrolimus dosages and concentration/dose ratio of four frequent MDR1 SNP possibly associated with P-gp function (T-129C in exon 1b, 1236C>T in exon 12, 2677G>T,A in exon 21, and 3435C>T in exon 26). As in the general population, the SNP in exons 12, 21, and 26 were frequent (16, 17.3, and 22.2% for the variant homozygous genotype, respectively) and exhibited incomplete linkage disequilibrium. One month after tacrolimus introduction, exon 21 SNP correlated significantly with the daily tacrolimus dose (P < or = 0.05) and the concentration/dose ratio (P < or = 0.02). Tacrolimus dose requirements were 40% higher in homozygous than wild-type patients for this SNP. The concentration/dose ratio was 36% lower in the wild-type patients, suggesting that, for a given dose, their tacrolimus blood concentration is lower. Haplotype analysis substantiated these results and suggested that exons 26 and 21 SNP may be associated with tacrolimus dose requirements. Genotype monitoring of the MDR1 gene reliably predicts the optimal dose of tacrolimus in renal transplant recipients and may predict the initial daily dose needed by individual patients to obtain adequate immunosuppression.
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PMID:Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients. 1281 58

The disposition of tacrolimus and the influence of cyclosporine, troleandomycin, and GF120918 (GG918, or N-[4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl]-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamine) on its hepatic disposition were examined in the isolated perfused rat liver. Livers from groups of rats were perfused in a recirculatory manner following a bolus dose of tacrolimus (100 microg), a substrate for P-glycoprotein (P-gp) and CYP3A, or with felodipine (200 microg), a substrate only for CYP3A. Perfusions of each substrate were also examined in groups of rats in the presence of the inhibitors: troleandomycin (20 microM, CYP3A inhibitor), GG918 (1 microM, P-gp inhibitor), or cyclosporine (10 microM, CYP3A and P-gp inhibitor). In all experiments, perfusate and bile were collected for 60 min. Tacrolimus, felodipine, and their primary metabolites were determined in perfusate and bile by liquid chromatography/tandem mass spectrometry. The area under the curve (AUC) from 0 to 30 min was determined. For the dual CYP3A and P-gp substrate, tacrolimus, AUC +/- S.D. was decreased from control (2,260 +/- 430 ng. min/ml) by GG918 (1,730 +/- 270 ng. min/ml, P < 0.05) and was increased by troleandomycin (5,200 +/- 2,470 ng. min/ml, P < 0.05) and cyclosporine (4,390 +/- 2,080 ng. min/ml, P < 0.05). For the exclusive CYP3A substrate, felodipine, AUC was unchanged from control by GG918 but increased by troleandomycin and cyclosporine. It is concluded that GG918 increased the hepatic exposure of tacrolimus by inhibiting the canalicular P-gp transport, whereas GG918 has no effect on hepatic disposition of felodipine. These results support our hypothesis that the hepatic metabolic clearance of a dual substrate will be increased by inhibiting the efflux transporter.
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PMID:Disposition of tacrolimus in isolated perfused rat liver: influence of troleandomycin, cyclosporine, and gg918. 1457 Jul 57

Tacrolimus is an immunosuppressant approved for the prevention of rejection following transplantation and is a substrate for CYP3A and P-glycoprotein. A pharmacokinetic interaction between St. John's wort (antidepressant herbal product and inducer of CYP3A and P-glycoprotein) and tacrolimus was evaluated in 10 healthy volunteers. The pharmacokinetics of tacrolimus were obtained from serial blood samples collected following single oral doses (0.1 mg/kg) prior to and during an 18-day concomitant St. John's wort dosing phase (300 mg orally three times daily). Coadministration of St. John's wort significantly decreased tacrolimus AUC (306.9 microg.h/L +/- 175.8 microg.h/L vs. 198.7 microg.h/L +/- 139.6 microg.h/L; p=0.004) and increased apparent oral clearance (349.0 mL/h/kg +/- 126.0 mL/h/kg vs. 586.4 mL/h/kg +/- 274.9 mL/h/kg; p=0.01) and apparent oral volume of distribution at steady state (11.5 L/kg +/- 4.3 L/kg vs. 17.6 L/kg +/- 9.6 L/kg; p=0.04). St. John's wort appears to induce tacrolimus metabolism, most likely through induction of CYP3A and P-glycoprotein.
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PMID:Effects of St. John's wort (Hypericum perforatum) on tacrolimus pharmacokinetics in healthy volunteers. 1468 46

Tacrolimus is a potent immunosuppressive agent used in lung transplantation and is a substrate for both P-glycoprotein (P-gp, encoded by the gene MDR1) and cytochrome (CYP) P4503A. A previous study by the authors identified a correlation between the tacrolimus blood level per dose with CYP3A5 and MDR1 gene polymorphisms in pediatric heart transplant patients. The objective of this study was to confirm the influence of these polymorphisms on tacrolimus dosing in adult lung transplant patients. Adult lung transplant patients who had been followed for at least 1 year after lung transplantation were studied. Tacrolimus blood level (ng/mL) per dose (mg/day) at 1, 3, 6, 9, and 12 months after transplantation was calculated as [L/D]. DNA was extracted from blood. MDR1 3435 CC, CT, and TT; MDR1 2677 GG, GT, and TT; and CYP3A5*1 (expressor) and *3 (nonexpressor) genotypes were determined by PCR amplification, direct sequencing, and sequence evaluation. Eighty-three patients were studied. At 1, 3, 6, 9, and 12 months after the transplant, a significant difference in [L/D] was found between the CYP3A5 expressor versus nonexpressor genotypes (mean +/- SD of 1.49 +/- 0.88 vs. 3.11 +/- 4.27, p = 0.01; 1.23 +/- 0.82 vs. 3.44 +/- 8.97, p = 0.05; 1.32 +/- 0.96 vs. 3.81 +/- 6.66, p = 0.005; 0.95 +/- 1.19 vs. 3.74 +/- 5.98, p = 0.0015; and 0.45 +/- 0.2 vs. 3.76 +/- 6.75, p = 0.0001, respectively). MDR1 G2677T and C3435T genotypes had only minimal effects on [L/D] at 1 and 3 months after transplantation. This study confirms the relationship of CYP3A5 polymorphisms to tacrolimus dosing in organ transplant patients. CYP3A5 expressor genotypes required a larger tacrolimus dose to achieve the same blood levels than the CYP3A5 nonexpressors at all time points during the first posttransplant year. This was not uniformly true for MDR1. The authors therefore conclude that tacrolimus dosing in adult lung transplant patients is associated with CYP3A5 gene polymorphisms.
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PMID:Tacrolimus dosing in adult lung transplant patients is related to cytochrome P4503A5 gene polymorphism. 1474 21


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