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)

To investigate the deleterious effects and possible mechanism of prenatal indole-3-carbinol (I3C) treatment on normal and tobacco-induced intrauterine growth restriction (IUGR) in rats, prenatal development toxicity in rats was studied. Expression of rat placental cytochrome P4501A1 (CYP1A1) and P-glycoprotein (Pgp), including mdr1a and mdr1b, were detected using reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Results showed that prenatal oral I3C had no significant effects on corpora lutea counts, implantation or the number of live, dead and resorbed fetuses in normal rats. Fetal malformations, sex ratio, neonatal body weights and physical developmental indices were also unchanged after prenatal I3C treatment. However, the offspring in the tobacco + I3C (4 mg kg(-1)) group showed lower average body weights (3.98+/-0.29 g) than tobacco control (4.48+/-0.11 g), and body and tail lengths lagged significantly behind those of the tobacco-smoke exposure only group. Expression of placental CYP1A1 mRNA by RT-PCR was not detected in the normal group, but was detected in the I3C, tobacco and tobacco + I3C groups. The level of CYP1A1 mRNA expression in the tobacco + I3C group was higher than in tobacco control. The level of mdr1a mRNA increased significantly in the I3C group when compared to normal control, and no obvious difference was detected between tobacco and tobacco + I3C groups. Expression of mdr1b mRNA was increased in the I3C and tobacco + I3C groups compared to their respective controls. Immunohistochemistry results showed that placental Pgp expression was enhanced in the I3C, tobacco and tobacco + I3C groups when compared to the normal control. The results suggest that prenatal oral I3C had no developmental toxicity but intensified fetal IUGR produced by prenatal tobacco-smoke exposure in rats. Up-regulations of placental CYP1A1 and Pgp by I3C might underlie the toxic mechanism.
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PMID:Indole-3-carbinol alters placental cytochrome P450 1A1 and P-glycoprotein levels in rats: a potential role in intensifying fetal intrauterine growth-retardation produced by tobacco smoke. 1680 64

Metabolism by cytochrome P4503A (CYP3A) and P-glycoprotein (P-gp)-mediated efflux are two important biochemical barriers to drug absorption from the intestine. CYP3A, the most important family of drug-metabolizing enzymes, shares many substrates with the efflux transporter P-gp. Although the individual impact of these two systems on drug disposition is routinely assessed, the effect of both systems acting together during intestinal absorption is difficult to ascertain. Pharmacokinetic theory predicts that the effect of efflux on overall metabolism depends on substrate concentrations relative to the respective kinetic parameters of these processes (i.e. affinities for transport and metabolism, as well as the capacities of these processes). Researchers have published conflicting findings on how efflux affects metabolism. Furthermore, the in vitro parameters that have been used to explain or predict this interation are more relevant for describing overall changes in extraction efficiency of the system (intestinal epithelium), rather than deconvoluting the effect of P-gp on CYP3A-mediated metabolism. Developing a more refined way to understand this interplay and its potential relevance to drug absorption is an important goal, as a large proportion of marketed drugs and many modern drug discovery candidates are known to be affected by one or both of these proteins.
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PMID:Deconvoluting the effects of P-glycoprotein on intestinal CYP3A: a major challenge. 1689 6

The control of leishmaniasis in absence of vaccine solely depends on the choice of chemotherapy. The major hurdle in successful leishmanial chemotherapy is emergence of drug resistance. Miltefosine, the first orally administrable anti-leishmanial drug, has shown the potential against drug-resistant strains of Leishmania. However, there are discrepancies regarding the involvement of P-glycoprotein (Pgp) and sensitivity of miltefosine in multiple drug-resistant (MDR) cell lines that overexpress Pgp in Leishmania. To address this, the effect of miltefosine in arsenite-resistant Leishmania donovani (Ld-As20) promastigotes displaying an MDR phenotype and overexpressing Pgp-like protein was investigated in the current study. Results indicate that Ld-As20 is sensitive to miltefosine. Miltefosine induces process of programmed cell death in Ld-As20 in a time-dependent manner as determined by cell shrinkage, externalization of phosphatidylserine and DNA fragmentation. Miltefosine treatment leads to loss of mitochondrial membrane potential and the release of cytochrome C with consequent activation of cellular proteases. Activation of cellular proteases resulted in activation of DNase that damaged kinetoplast DNA and induced dyskinetoplasty. These data indicate that miltefosine causes apoptosis-like death in arsenite-resistant L. donovani.
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PMID:Miltefosine induces apoptosis in arsenite-resistant Leishmania donovani promastigotes through mitochondrial dysfunction. 1716 39

By searching the literatures, it was found that a total of 32 drugs interacting with herbal medicines in humans. These drugs mainly include anticoagulants (warfarin, aspirin and phenprocoumon), sedatives and antidepressants (midazolam, alprazolam and amitriptyline), oral contraceptives, anti-HIV agents (indinavir, ritonavir and saquinavir), cardiovascular drug (digoxin), immunosuppressants (cyclosporine and tacrolimus) and anticancer drugs (imatinib and irinotecan). Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (PgP) and many of which have narrow therapeutic indices. However, several drugs including acetaminophen, carbamazepine, mycophenolic acid, and pravastatin did not interact with herbs. Both pharmacokinetic (e.g. induction of hepatic CYPs and intestinal PgP) and/or pharmacodynamic mechanisms (e.g. synergistic or antagonistic interaction on the same drug target) may be involved in drug-herb interactions, leading of altered drug clearance, response and toxicity. Toxicity arising from drug-herb interactions may be minor, moderate, or even fatal, depending on a number of factors associated with the patients, herbs and drugs. Predicting drug-herb interactions, timely identification of drugs that interact with herbs, and therapeutic drug monitoring may minimize toxic drug-herb interactions. It is likely to predict pharmacokinetic herb-drug interactions by following the pharmacokinetic principles and using proper models that are used for predicting drug-drug interactions. Identification of drugs that interact with herbs can be incorporated into the early stages of drug development. A fourth approach for circumventing toxicity arising from drug-herb interactions is proper design of drugs with minimal potential for herbal interaction. So-called "hard drugs" that are not metabolized by CYPs and not transported by PgP are believed not to interact with herbs due to their unique pharmacokinetic properties. More studies are needed and new approached are required to minimize toxicity arising from drug-herb interactions.
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PMID:Drug-herb interactions: eliminating toxicity with hard drug design. 1716 68

Tacrolimus, an immunosuppressant used after organ transplantation, has a narrow therapeutic range and its pharmacokinetic variability complicates its daily dose assessment. P-glycoprotein (P-gp), encoded by the adenosine triphosphate-binding cassette B1 (ABCB1) and the cytochrome (CYP) 3A4 and 3A5 enzymes appears to play a role in the tacrolimus metabolism. In the present study, two different renal transplant recipient groups were used to examine the influence of ABCB1 and CYP3A polymorphisms on the daily tacrolimus dose and several pharmacokinetic parameters. In total 63 Caucasian renal transplant recipients divided into 26 early [median (range) of the days since transplantation - 16 (3-74)] and 37 late [median (range) of the days since transplantation - 1465 (453-4128)] post-transplant recipients were genotyped for ABCB1 and CYP3A polymorphisms. The pharmacokinetic parameters of tacrolimus were determined for all renal transplant recipients and correlated with their corresponding genotypes. A significant difference in allele frequencies of the CYP3A4*1B (P = 0.028) and CYP3A5*1 (P = 0.022) alleles was observed between the early and late post-transplant recipient groups. Significantly higher dose-normalized trough levels (dnC(0)), dose-normalized area under the curve (dnAUC(0-12)), and dose-normalized maximum concentration (dnC(max)) were observed for carriers of the CYP3A5*3 variant allele in both renal transplant patient groups. Except for the daily tacrolimus dose (P = 0.025) no significant differences were observed for carriers of the CYP3A4*1B variant allele. Neither the individual ABCB1 polymorphisms nor the ABCB1 haplotypes were associated with any pharmacokinetic parameter. We noticed that patients carrying a CYP3A5*1 allele require a twofold higher tacrolimus dose compared with homozygous carriers of the CYP3A5*3 variant allele to maintain the target dnAUC(0-12). Therefore, genotyping for the CYP3A5*3 variant allele can contribute to a better and more individualized immunosuppressive therapy in transplant patients.
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PMID:Tacrolimus pharmacokinetics and pharmacogenetics: influence of adenosine triphosphate-binding cassette B1 (ABCB1) and cytochrome (CYP) 3A polymorphisms. 1763 82

To date, several clinically important drugs have been identified that interact with commonly used herbs. These drugs include (among others) warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus and irinotecan. Importantly, many of these drugs have very narrow therapeutic indices. Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). Because drug-herb interactions can significantly affect circulating levels of drug and, hence, alter the clinical outcome, the identification of drugs that interact with commonly used herbal medicines has important implications in drug development. In silico, in vitro, animal and human studies are often used to identify drug interactions with herbs. We propose that drug-herb and herb-CYP interaction studies should be incorporated into drug development.
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PMID:Identification of drugs that interact with herbs in drug development. 1770 49

The effect of silymarin pretreatment on the pharmacokinetics of ranitidine was investigated in 12 healthy male human volunteers aged 19-26 years. After an overnight fast, ranitidine 150 mg was administered to the volunteers either alone or after 7 days pretreatment with thrice daily dose of 140 mg silymarin. The wash-out period between each treatment was 7 days. Serum levels of ranitidine were determined by HPLC. Pharmacokinetic parameters were determined based on non-compartmental model analysis using the computer program KINETICA. There was no influence of silymarin on the pharmacokinetics of ranitidine. Concomitant administration of silymarin at this dosage did not alter ranitidine C(max) and AUC(0-infinity). There was a significant difference in area under the first moment curve (AUMC) and mean residence time. This result is useful in predicting the interaction of silymarin with other cytochrome 3A4 and P-glycoprotein substrates at normal dosage.
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PMID:Effect of silymarin on the oral bioavailability of ranitidine in healthy human volunteers. 1770 67

To elucidate the possible metabolic mechanism of intrauterine growth retardation induced by nicotine, this study determines the effects of prenatal nicotine exposure on fetal development and cytochrome P4501A1 (CYP1A1), CYP2E1, and P-glycoprotein (Pgp) expression in maternal liver and placenta. Pregnant rats were given 1.0 mg/kg nicotine subcutaneously twice a day from gestational day (GD) 8 to GD 15, 18, or 21. In nicotine-treated groups, fetal developmental parameters including body weight were significantly lower. The activities of CYP1A1 and CYP2E1 in maternal liver microsomes in nicotine-treated groups increased significantly with progressing gestation when compared with the corresponding control, but returned to the level similar to the control in late pregnancy. Nicotine-treated groups induced pathological changes and increased malondialdehyde (MDA) content in the placenta when compared with the control. The gene expressions of CYP1A1 and CYP2E1 in the placenta increased significantly in nicotine-treated groups on GD 15 and GD 18, but returned to the level similar to the corresponding control on GD 21. In nicotine group, there was a decrease of mdr1a expression on GD 15, GD 18, and GD 21, with the most significant decrease on GD 15. In contrast, no significant difference was found in mdr1b mRNA expression between the nicotine-treated animals and the corresponding control. In comparison with the corresponding control, the placental Pgp protein significantly decreased on GD 15 and GD 18. Our results showed that prenatal nicotine exposure resulted in inhibition of fetal growth significantly. The induction of CYP2E1 and CYP1A1 gene expression by nicotine in the maternal liver and placenta may be involved with the observed increase in oxidative stress and lipid peroxidation. The inhibition of the placental Pgp expression by nicotine may also contribute to an increased susceptibility of the fetus to environmental toxins.
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PMID:Growth retardation of fetal rats exposed to nicotine in utero: possible involvement of CYP1A1, CYP2E1, and P-glycoprotein. 1844 69

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.
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PMID:Effects of cyclosporine a on single-dose pharmacokinetics of intravenous itraconazole in patients with hematologic malignancies. 1852 Jun 1

St. John's wort (Hypericum perforatum, SJW) is one of the most commonly used herbal antidepressants for the treatment of minor to moderate depression. Limited clinical trials suggest that hypericum and standard antidepressants have similar beneficial effects, but current evidence regarding the antidepression effects of SJW extracts is inconsistent. A major safety concern about SJW is its ability to alter the pharmacokinetics and/or clinical response of a variety of clinically important drugs. This review highlights and updates the knowledge regarding drug interactions with SJW by a systematic review of all the available evidence, including worldwide published literature and spontaneous case reports. A number of clinically significant interactions of SJW have been identified with conventional drugs. These interactions often result in a decrease in the concentration or effect of the combined drug, most probably due to the induction of cytochrome P450s (CYPs) and the key drug transporter P-glycoprotein (P-gp) by the major active constituents in SJW. SJW is a potent inducer of human CYP3A4 and P-gp in vitro and in vivo. In addition, pharmacodynamic interactions of SJW with some drugs (e.g. selective serotonin re-uptake inhibitors) have been identified, which are associated with an increased risk of adverse reactions. Since potential interactions of SJW with conventional drugs is a major safety concern, it is important to minimize and avoid these interactions by taking appropriate approaches. These include systematic research to identify SJW-drug interaction; close therapeutic drug monitoring when SJW is combined with conventional drugs with a narrow therapeutic window; proper dose and regimen adjustment; patient education and communication between the patient and physician; design of new preparations of SJW without inducing ability of CYP3A4 and P-gp while retaining its bioactivity; and appropriate regulation in herbal safety and efficacy. Further clinical and mechanistic studies are warranted to explore the interaction of SJW with other important drugs and clinical significance.
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PMID:An update on clinical drug interactions with the herbal antidepressant St. John's wort. 1853 76


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