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)

The effect of an in vivo treatment with two commonly employed drugs that are P-glycoprotein substrates, verapamil and rifampicin, on Ehrlich ascites carcinoma cells, was evaluated. Ehrlich ascites carcinoma cells were inoculated i.p. in CD-1 mice and animals were orally treated for 10 days with rifampicin (60 mg/kg/day) or verapamil (6 mg/kg/day). In the harvested cells the transcripts for mdr1a and mrp1, but not those for mdr1b, mrp2 and CYP3A, were detected, and treatment with verapamil or rifampicin did not modify the levels of the transcripts. On the contrary, an increased expression of P-glycoprotein was observed at the protein level with Western blot. The intracellular uptake of doxorubicin, a P-glycoprotein and MRP substrate, was significantly lower in cells obtained from treated animals in comparison with cells obtained from controls; in addition, the uptake was increased by a pretreatment with verapamil. The survival time of control animals implanted with untreated cells was similar to that of animals inoculated with cells obtained from rifampicin treated animals, however, the antineoplastic effect of doxorubicin was significanly higher in control animals. A treatment with rifampicin or verapamil in Ehrlich ascites tumor confers resistance to the antineoplastic drug doxorubicin, probably through an increased expression of P-glycoprotein.
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PMID:Rifampicin and verapamil induce the expression of P-glycoprotein in vivo in Ehrlich ascites tumor cells. 1503 67

Sirolimus is primarily used as a rescue agent in pediatric transplant recipients, particularly in cases of cyclosporine or tacrolimus toxicity. Preliminary data indicate a higher apparent oral clearance in younger children (4-10 years of age). Various drug interactions have been described between sirolimus and drugs that are substrates/inhibitors or inducers of CYP3A and the P-glycoprotein transporter. Close monitoring of trough sirolimus blood levels is therefore recommended for pediatric transplant recipients. In de novo adult kidney transplant recipients on triple therapy with cyclosporine, corticosteroids and sirolimus, a therapeutic window of 4-12 microg/l is recommended for sirolimus trough concentrations determined by HPLC or LC/MS-MS. In maintenance adult patients after conversion to a calcineurin inhibitor-free regimen, sirolimus trough concentrations of 5-10 microg/l are proposed in combination with mycophenolate mofetil. These therapeutic ranges may also serve as a guide for pediatric renal transplant recipients. The concept of C2 monitoring still needs to be critically evaluated in pediatric patients. The crucial importance of achieving an adequate cyclosporine exposure early after transplantation has been demonstrated for adult transplant recipients. A cyclosporine concentration taken 2 h after dosing is a good surrogate marker of the AUC0-4h in adults. Various clinical studies have shown that in pediatric patients, the C2 concentration shows a substantially better correlation with cyclosporine exposure compared to the trough level (C0). In an outcome study with pediatric renal transplant recipients, it could be demonstrated that the AUC(0-4h) was a predictor of acute rejection in the first 3 weeks after transplantation, whereas C2 levels showed no significant association. Abbreviated AUC strategies may be preferable for optimization of CsA exposure in pediatric patients.
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PMID:Immunosuppressive drug monitoring of sirolimus and cyclosporine in pediatric patients. 1518 89

The role of P-glycoprotein (P-gp) on the distribution of the benzodiazepine triazolam (TRZ) and the azole antifungal agent ketoconazole (KET), and on the TRZ-KET interaction, was studied using mdr1a(-) or mdr1a/b(-/-) mice (P-gp-deficient mice) and matched controls. TRZ and KET also were studied in Caco-2 cells in Transwell culture. After single i.p. injections of TRZ or KET in separate groups of control mice, brain concentrations of TRZ exceeded those in serum [brain/serum area under the concentration curve (AUC) ratio, 5.0], whereas brain/serum AUC ratios for KET were approximately 0.5. On the basis of single time points, brain concentrations of TRZ, or brain/serum ratios, were similar in P-gp-deficient animals compared with controls, whereas P-gp-deficient animals had significantly higher KET brain concentrations and brain/serum ratios. Coadministration of KET with TRZ increased TRZ concentrations in serum, liver, and brain, both in controls and in P-gp-deficient animals, probably attributable to impairment by KET of CYP3A-mediated clearance of TRZ. However, KET did not increase brain/serum ratios of TRZ in either group. In Caco-2 cells, basal-to-apical flux of TRZ was higher than apical-to-basal flux. However, verapamil (100 microM) did not alter flux in either direction. KET inhibited basal-to-apical transport of rho-damine-123, with a 50% inhibitory concentration of 2.7 microM. Thus, TRZ does not appear to undergo measurable blood-brain barrier efflux transport by P-gp in this animal model. KET impairs clearance of TRZ but does not increase tissue uptake. However, KET itself may be a substrate for efflux transport at the blood-brain barrier.
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PMID:Interaction of triazolam and ketoconazole in P-glycoprotein-deficient mice. 1525 4

P-glycoprotein (P-gp) and CYP3A have considerable overlap in inducers in vitro. Characterizing P-gp induction in vivo and potential coregulation with CYP3A are important goals for predicting drug interactions. This study examined P-gp expression in mouse tissues and potential coinduction with CYP3A following oral treatment with 1 of 7 prototypical inducing agents for 5 days. P-gp expression in brain or liver was not induced by any treatment as determined by Western blot, whereas dexamethasone, pregnenolone-16alpha-carbonitrile (PCN), St. John's wort (SJW), and rifampin induced hepatic CYP3A expression. In intestine, rifampin and SJW induced P-gp expression 3.7- and 1.6-fold and CYP3A 3.5- and 2.4-fold, respectively, whereas dexamethasone and PCN induced CYP3A only. These observations suggest that P-gp in mouse small intestine is inducible by some, but not all, CYP3A inducers, whereas P-gp expression in liver or brain is not readily induced. Intriguingly, rifampin and SJW, both activators of the human pregnane X receptor (PXR), induced CYP3A in both liver and intestine but induced P-gp only in intestine, whereas PCN, an activator of murine PXR, did not induce P-gp in any tissue. Rifampin disposition was evaluated, and hepatic exposure to rifampin was comparable to intestine; in contrast, brain concentrations were low. Overall, these observations demonstrate that P-gp induction in vivo is tissue-specific; furthermore, there is a disconnect between P-gp induction and CYP3A induction that is tissue- and inducer-dependent, suggesting that PXR activation alone is insufficient for P-gp induction in vivo. Tissue-specific factors and inducer pharmacokinetic/pharmacodynamic properties may underlie these observations.
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PMID:Effect of prototypical inducing agents on P-glycoprotein and CYP3A expression in mouse tissues. 1531 43

Tacrolimus is characterized by a highly variable oral bioavailability and narrow therapeutic window. Tacrolimus absorption from the gastrointestinal tract is to a large extent determined by the genotypic, phenotypic, and functional expression of P-glycoprotein and CYP3A in the gut wall and liver. It is disputed whether the gastric emptying rate per se is important for determining oral bioavailability of tacrolimus and whether delayed gastric emptying is clinically relevant for therapeutic drug dosing. We conducted a pharmacokinetic study in 50 renal recipients, measuring simultaneously the rate of gastric emptying using a carbon-14-octanoic acid breath test and quantifying drug exposure by area under the concentration-time curve sampling. Gastric half emptying time (t1/2) significantly correlated with time to reach maximum blood tacrolimus (tmax) concentration (r2 = 0.30; p < 0.0001), whereas the gastric emptying coefficient, reflecting the overall gastric emptying rate, showed a weak inverse correlation with tmax (r2 = 0.14; p = 0.007). The time-dependent rate of gastric emptying strongly correlated with the simultaneously measured blood tacrolimus concentration over the first 4 h after oral drug administration (r2 = 0.96; p < 0.0001). Comparison between patients with and without delayed gastric emptying confirmed that maximum blood tacrolimus concentration was reached significantly more slowly in the former group (tmax, 2 +/- 1 h versus 1.48 +/- 0.68 h; p = 0.04), whereas the extent of tacrolimus absorption was not different. Despite a strong association between gastric emptying rate and the timing of tacrolimus absorption from the gut in stable recipients, gastric emptying rate does not affect the total extent of drug absorption and is not responsible for significant alterations in drug exposure, even in situations of delayed gastric emptying.
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PMID:The rate of gastric emptying determines the timing but not the extent of oral tacrolimus absorption: simultaneous measurement of drug exposure and gastric emptying by carbon-14-octanoic acid breath test in stable renal allograft recipients. 1538 95

The effects of tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen on transport attributable to P-glycoprotein were studied using Caco-2 cell monolayers in a transwell system, with rhodamine-123 as an index substrate for inhibition studies. The three compounds did not demonstrate differential flux between basal-apical and apical-basal directions in Caco-2 monolayers. The mean IC50 values for inhibition of rhodamine-123 transport were: 29 microM for tamoxifen; 26 microM for N-desmethyltamoxifen; and 7.4 microM for 4-hydroxytamoxifen. The three compounds were also evaluated as potential inhibitors of human CYP3A based on an in vitro model using triazolam hydroxylation by human liver microsomes as an index reaction. Mean (+/-SE) IC50 values versus formation of alpha-hydroxy-triazolam and 4-hydroxy-triazolam in human liver microsomes were, respectively: 23.5 (+/-3.9) and 18.4 (+/-5.3) microM for tamoxifen; 10.2 (+/-1.7) and 9.2 (+/-1.5) microM for N-desmethyltamoxifen; and 2.6 (+/-0.5) and 2.7 (+/-0.3) microM for 4-hydroxytamoxifen. Thus, tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen, do not appear to be substrates for transport by P-glycoprotein. However, tamoxifen has the potential to inhibit transport mediated by P-glycoprotein as well as CYP3A-mediated metabolism. Inhibitory effects of the principal metabolites, N-desmethyltamoxifen and 4-hydroxytamoxifen, may exceed those of the parent drug. Tamoxifen, and possibly its metabolites, may have the potential to cause drug interactions by inhibiting both drug transport and metabolism. This possibility requires further evaluation in clinical studies.
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PMID:Interactions of tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen with P-glycoprotein and CYP3A. 1538 82

Methoxymorpholinyl doxorubicin (MMDX) is a novel liver cytochrome P450 (P450)-activated anticancer prodrug whose toxicity toward cultured tumor cells can be potentiated up to 100-fold by incubation with liver microsomes and NADPH. In the present study, a panel of human liver microsomes activated MMDX with potentiation ratios directly correlated to the CYP3A-dependent testosterone 6beta-hydroxylase activity of each liver sample. Microsome-activated MMDX exhibited nanomolar IC(50) values in growth-inhibition assays of human tumor cell lines representing multiple tissues of origin: lung (A549 cells), brain (U251 cells), colon (LS180 cells), and breast (MCF-7 cells). Analysis of individual cDNA-expressed CYP3A enzymes revealed that rat CYP3A1 and human CYP3A4 activated MMDX more efficiently than rat CYP3A2 and that human P450s 3A5 and 3A7 displayed little or no activity. MMDX cytotoxicity was substantially increased in Chinese hamster ovary cells after stable expression of CYP3A4 in combination with P450 reductase. CYP3A activation of MMDX abolished the parent drug's residual cross-resistance in a doxorubicin-resistant MCF-7 cell line that overexpresses P-glycoprotein. CYP3A-activated MMDX displayed a comparatively high intrinsic stability, with a t(1/2) of approximately 5.5 h at 37 degrees C. MMDX was rapidly activated by CYP3A at low ( approximately 1-5 nM) prodrug concentrations, with 100% tumor cell kill obtained after as short as a 2-h exposure to the activated metabolite. These findings demonstrate that MMDX can be activated by CYP3A metabolism to a potent, long-lived, and cell-permeable cytotoxic metabolite and suggest that this anthracycline prodrug may be used in combination with CYP3A4 in a P450 prodrug activation-based gene therapy for cancer treatment.
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PMID:Antitumor activity of methoxymorpholinyl doxorubicin: potentiation by cytochrome P450 3A metabolism. 1546 24

We investigated the effect of Apocynum venetum L. extract (AV) on the activity of cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp). The plasma concentration of nifedipine (NF), which is a substrate for CYP3A, did not change after oral administration with AV (3.3 mg/kg). Also, AV (3.3 and 33 mg/kg) did not affect the intestinal absorption of NF. In the rats treated with multiple administrations (15 mg/kg/d) of St. John's wort extract (SJW) for 2 weeks, the plasma concentration of NF after oral administration was significantly decreased. On the other hand, there was no significant differences in the pharmacokinetic parameters of NF between AV-treated (3.3 mg/kg/d) and none-treated rats. Furthermore, the intestinal absorption of methylprednisolone, which is a substrate for P-gp, was not affected by AV treatment for 2 weeks. These results suggest that, unlike SJW, the recommended dose of AV (3.3 mg/kg/d) would not influence hepatic CYP3A and intestinal P-gp in rats.
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PMID:Apocynum venetum extract does not induce CYP3A and P-glycoprotein in rats. 1546 12

We examined the effects of high-dose methylprednisolone on the bioavailability of orally administered ciclosporin in rats. To emulate the clinical protocol of methylprednisolone pulse therapy, methylprednisolone sodium succinate (MPS), a prodrug of methylprednisolone, was intravenously administered as repeated doses (66.3 mg kg(-1)) for 3 days. The area under the blood ciclosporin concentration versus time curve after oral administration was significantly reduced by 60% by pulse treatment with MPS. Based on our previous finding that the total body clearance of ciclosporin was reduced by about 20% by the same methylprednisolone pulse protocol, the extent of reduction in the oral bioavailability of ciclosporin was estimated to be approximately 50%, indicating a drug interaction between high-dose methylprednisolone and orally administered ciclosporin, which affected the absorption process. In rats treated with MPS, an in-situ efflux experiment using rhodamine-123 demonstrated that the reverse transport function of P-glycoprotein (P-gp) in the small intestine was significantly enhanced, although there was no significant increase in the intestinal microsomal activity of triazolam alpha- and 4-hydroxylation, metabolic probes for CYP3A. In addition, a significant decrease was observed in the amount of secreted bile acids serving as an enhancer of gastrointestinal absorption of ciclosporin in MPS treatment. To directly estimate the absorptive capacity, an in-situ absorption test was conducted using a closed-loop of small intestine in control and MPS-treated rats. Intestinal absorption of ciclosporin was significantly decreased, not only in the absence of bile flow but also by treatment with MPS, which well reflected the change in the in-vivo pharmacokinetic behaviour of ciclosporin after methylprednisolone pulsing. These results demonstrate that bioavailability of ciclosporin is markedly reduced by MPS pulse treatment, and the mechanism of this interaction was confirmed to involve enhancement of small-intestinal P-gp function and decrease in bile secretion.
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PMID:Decrease in oral bioavailability of ciclosporin by intravenous pulse of methylprednisolone succinate in rats. 1548 40

The effects of Ginkgo biloba leaf extract (GBE), one of the most widely used herbal dietary supplements in Japan and the United States, on the pharmacokinetics of nifedipine (NFP), a typical probe of P450 (CYP) 3A, but not a substrate of the multidrug transporter P-glycoprotein (P-gp), were studied using rats. Simultaneous oral treatment with GBE (20 mg/kg) did not affect the pharmacokinetics after intravenous administration of NFP (2.5 mg/kg). However, the maximal plasma NFP concentration, the area under the concentration-time curve and absolute bioavailability after oral administration of NFP (5 mg/kg) were significantly increased by simultaneous oral treatment with GBE, approximately 1.6-fold, 1.6-fold and 2.1-fold, respectively. These results suggest that the concomitant oral use of GBE appeared to reduce the first-pass metabolism of orally administered NFP, by inhibiting CYP3A, possibly but not P-gp, in rats.
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PMID:Studies on interactions between functional foods or dietary supplements and medicines. III. Effects of ginkgo biloba leaf extract on the pharmacokinetics of nifedipine in rats. 1557 30


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