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 novel substituted imidazole compound, OC144-093 exhibits potent biological activity in vitro and in vivo for reversal of P-glycoprotein (PgP) based resistance to cancer chemotherapy. Its mechanism of action relies upon its inhibitory interaction with the mdr1 gene product, a known mediator of multidrug resistance (MDR). Overlapping substrate specificities and tissue distribution of cytochrome P450 3A (CYP3A) and PgP indicate the potential for drug-drug interactions when modulator and anticancer agent are co-administered. We have examined the metabolism of OC144-093 in vitro using human liver microsomes to determine if CYP3A is involved. Our results show that OC144-093 is converted to one major metabolite (M1) in human liver microsomes which was identified by LCMS to be the O-deethylated derivative. Km and Vmax for O-deethylation were determined as 3.96+/-0.67 microM and 32.08+/-9.73 pmol/mg protein/min, respectively (n=3). Correlation studies conducted in a panel of human livers phenotyped for specific P450 enzyme activity showed a significant relationship between M1 formation and the activity of CYP2C9, CYP2B6, CYP2E1 and CYP3A4. Treatment of microsomes with carbon monoxide gas inhibited M1 formation and diethyldithiocarbamate and ketoconazole (>3 microM), non-specific CYP inhibitors, gave IC50 values of 124.4+/-21.6 microM and 25.3+/-3.2 microM respectively for the inhibition of O-deethylation, also implicating the involvement of CYP enzymes. Specific CYP inhibitors of CYP3A4 were essentially non-inhibitory to M1 formation. We can conclude therefore that OC144-093 is not extensively metabolised in human liver microsomes although conversion to its O-deethylated derivative does occur. Our data indicates that this conversion is not mediated by CYP3A4.
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PMID:Assessment of the involvement of CYP3A in the vitro metabolism of a new modulator of MDR in cancer chemotherapy, OC144-193, by human liver microsomes. 1180 70

Patient-controlled analgesia (PCA) has become standard procedure in the clinical treatment of pain. Its widespread use in patients with all kinds of diseases opens a variety of possible interactions between analgesics used for PCA and other drugs that might be administered concomitantly to the patient. Many of these drug interactions are of little clinical importance. However, some drug interactions have been reported to result in serious clinical problems. Drug interactions can either predominantly affect the pharmacokinetics or pharmacodynamics of the drug. Most important pharmacokinetic drug interactions occur at the level of drug metabolism or protein binding. Acceleration of methadone metabolism caused by cytochrome P450 (CYP) 3A4 induction by antiretroviral drugs or rifampicin (rifampin) has caused methadone withdrawal symptoms. Lack of morphine formation from codeine as a result of CYP2D6 inhibition by quinidine results in an almost complete loss of the analgesic effects of codeine. Alterations of methadone protein binding caused by an inhibition of alpha1-acid glycoprotein synthesis by alkylating substances are another possibility for predominantly pharmacokinetically based drug interactions during PCA. Furthermore, inhibition of P-glycoprotein by anticancer drugs could result in altered transmembrane transport of morphine, methadone or fentanyl, although this has not been shown to be of clinical relevance. Synergistic effects of systemically administered opioids with spinally or topically delivered opioids or anaesthetics have been reported frequently. The same is true for the opioid-sparing effects of coadministered non-opioid analgesics. Antidepressants, anticonvulsants or alpha2-adrenoreceptor agonists have also been shown to exert additive analgesic effects when administered together with an opioid. Inconsistent findings, however, are reported regarding the treatment of patients with opioid-induced nausea and sedation, since coadministration of antiemetics either increased or decreased the respective adverse effects or revealed additional unwanted drug effects.
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PMID:Drug interactions with patient-controlled analgesia. 1182 96

The use of highly active antiretroviral therapy, the combination of at least three different antiretroviral drugs for the treatment of HIV-1 infection, has greatly improved the prognosis for HIV-1-infected patients. The efficacy of a combination of a protease inhibitor (PI) plus two nucleoside analogue reverse transcriptase inhibitors has been well established over a period of up to 3 years. However, virological treatment failure has been reported in 40-60% of unselected patients within 1 year after initiation of a PI-containing regimen. This observation may, at least in part, be attributed to the poor pharmacokinetic characteristics of the PIs. Given as a single agent the PIs have several pharmacokinetic limitations; relatively short plasma-elimination half-lives and a modest and variable oral bioavailability, which is, for some of the PIs, influenced by food. To overcome these suboptimal pharmacokinetics, high doses (requiring large numbers of pills) must be ingested, often with food restrictions, which complicates patient adherence to the prescribed regimen. Positive drug-drug interactions increase the exposure to the PIs, allowing administration of lower doses at reduced dosing frequencies with less dietary restrictions. In addition to increasing the potency of an antiretroviral regimen, combinations of PIs may enhance patient adherence, both of which will contribute to a more durable suppression of viral replication. The favourable pharmacokinetics of PIs in combination are a result of interactions through cytochrome P450 3A4 (CYP3A4) isoenzymes and, possibly, the multi-drug transporting P-glycoprotein (P-gp). Antiretroviral synergy between PIs and non-overlapping primary resistance patterns in the HIV-1 protease genome may further enhance the antiretroviral potency and durability of combinations of PIs. Many combinations contain ritonavir because this PI has the most pronounced inhibiting effects on CYP3A4. The combination of saquinavir and ritonavir, both in a dose of 400 mg twice-a-day, is the most studied double PI combination, with clinical experience extending over 3 years. Combination of a PI with a low dose of ritonavir (< or = 400 mg/day), only to boost its pharmacokinetic properties, seems an attractive option for patients who cannot tolerate higher doses of ritonavir. A recently introduced PI, lopinavir, has been co-formulated with low-dose ritonavir, which allows for a convenient three-capsules, twice-a-day dosing regimen. In an attempt to prolong suppression of viral replication combinations of PIs are becoming increasingly popular. However, further clinical studies are needed to identify the optimal combinations for treatment of antiretroviral naive and experienced HIV-1-infected patients. This review covers combinations of saquinavir, indinavir, nelfinavir, amprenavir and lopinavir with different doses of ritonavir, as well as the combinations of saquinavir and indinavir with nelfinavir.
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PMID:Combination of protease inhibitors for the treatment of HIV-1-infected patients: a review of pharmacokinetics and clinical experience. 1187 3

The pharmacokinetics of valspodar (PSC 833), a selective second-generation P-glycoprotein modulator, was evaluated as part of a Phase I study to modulate paclitaxel therapy in 15 patients with refractory malignancies. Valspodar was given intravenously at 1.42 mg/kg/h for 2 hours, followed by a 27-hour continuous infusion at 0.42 mg/kg/h. Serial blood samples were obtained after intravenous infusion of valspodar and paclitaxel. Valspodar disposition was best described by a linear two-compartment model. The median (range) valspodar clearance was 0.40 ml/min/kg (0.07-1.40 ml/min/kg). The 20-fold interpatient variability in valspodar clearance was not correlated with age, body weight, orgender but might be associated with coadministered medications that were metabolized via cytochrome P450 3A-mediated elimination. Valspodar whole-blood concentrations were maintained above the target threshold of 1000 ng/ml for a median of 32 hours. The pharmacokinetic model generated from this study allows for application in future studies to optimize the use of valspodar.
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PMID:Pharmacokinetic study of infusional valspodar. 1193 66

Using some calcium channel blockers of the dihydropyridine-type (amlodipine (CAS 88150-42-9, felodipine (CAS 72508-76-3), lercanidipine (CAS 100472-26-7), nifedipine (CAS 21829-25-4), nitrendipine (CAS 39562-70-4)) as example the interaction potential of these substances will be compared in terms of affecting metabolism and transport of drugs. The cytochrome P450 (CYP) isoform CYP3A4 and the P-glycoprotein (P-gp), respectively, will have a high impact for both pharmacokinetic processes, as all 5 calcium channel blockers are substrates of CYP3A4 and in addition nifedipine, nitrendipine and felodipine represent inhibitors of P-gp, which can cause an increase in the plasma levels of digoxin (model substrate of P-gp). If inducers (e.g. rifampicin, anticonvulsants, St John's wort) or inhibitors (ketoconazole, itraconazole, erythromycin, clarithromycin, nefazodone, fluvoxamine, fluoxetine, sertraline, ritonavir, indinavir, amprenavir, saquinavir or grapefruit juice) of CYP3A4 are concomitantly administered pharmacokinetic interactions could be expected to a variable extent. Some alternative drugs are mentioned which will not affect CYP3A4. In addition to these putative pharmacokinetic interactions also pharmacodynamic interactions with other cardiovascular active substances might be considered and some caution should be exercised if vasodilators are given as comedication.
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PMID:Interaction potential of lercanidipine, a new vasoselective dihydropyridine calcium antagonist. 1196 41

The intestinal mucosa is capable of metabolising drugs via phase I and II reactions. Increasingly, as a result of in vitro and in vivo (animal and human) data, the intestinal mucosa is being implicated as a major metabolic organ for some drugs. This has been supported by clinical studies of orally administered drugs (well-known examples include cyclosporin, midazolam, nifedipine and tacrolimus) where intestinal drug metabolism has significantly reduced oral bioavailability. This review discusses the intestinal properties and processes that contribute to drug metabolism. An understanding of the interplay between the processes controlling absorption, metabolism and P-glycoprotein-mediated efflux from the intestinal mucosa into the intestinal lumen facilitates determination of the extent of the intestinal contribution to first-pass metabolism. The clinical relevance of intestinal metabolism, however, depends on the relative importance of the metabolic pathway involved, the therapeutic index of the drug and the inherent inter- and intra-individual variability. This variability can stem from genetic (metabolising enzyme polymorphisms) and/or non-genetic (including concomitant drug and food intake, route of administration) sources. An overwhelming proportion of clinically relevant drug interactions where the intestine has been implicated as a major contributor to first-pass metabolism involve drugs that undergo cytochrome P450 (CYP) 3A4-mediated biotransformation and are substrates for the efflux transporter P-glycoprotein. Much work is yet to be done in characterising the clinical impact of other enzyme systems on drug therapy. In order to achieve this, the first-pass contributions of the intestine and liver must be successfully decoupled.
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PMID:The mucosa of the small intestine: how clinically relevant as an organ of drug metabolism? 1197 43

Inhibitors of P-glycoprotein (P-gp) (verapamil) or cytochrome P-450 (ketoconazole) may reduce IL2 production and T lymphocyte proliferation in vitro. We have examined the effects of chronic oral administration of these drugs and of the cytochrome P450 inductor, carbamazepine, on the hematological and immunological parameters of mice. We found no changes after giving the mice 0.12 mg verapamil, 0.85 mg ketoconazole, or 0.514 mg carbamazepine per mouse for 4 weeks (5 days/week). But giving the drugs for an additional 7 weeks at 0.6 mg (verapamil), 4.25 mg (ketoconazole) or 2.57 mg/mouse (carbamazepine), resulted in significant decreases in monocytes in the verapamil treated group (-51%) and in CD4+ cells in the carbamazepine group (-35%). Chronic oral administration of these drugs reduced the lymphocyte counts of mice by 10-18% and their NK counts by 10-16%. These changes could be due to changes in P-gp function in the transport of IL2, with decreases caused by verapamil and ketoconazole.
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PMID:Chronic administration of verapamil, ketoconazole and carbamazepine: impact on immunological parameters. 1199 17

Gender-related differences in pharmacokinetics have frequently been considered as potentially important determinants for the clinical effectiveness of drug therapy. The mechanistic processes underlying gender-specific pharmacokinetics can be divided into molecular and physiological factors. Major molecular factors involved in drug disposition include drug transporters and drug-metabolising enzymes. Men seem to have a higher activity relative to women for the cytochrome P450 (CYP) isoenzymes CYP1A2 and potentially CYP2E1, for the drug efflux transporter P-glycoprotein, and for some isoforms of glucuronosyltransferases and sulfotransferases. Women were suggested to have a higher CYP2D6 activity. No major gender-specific differences seem to exist for CYP2C19 and CYP3A. The often-described higher hepatic clearance in women compared with men for substrates of CYP3A and P-glycoprotein, such as erythromycin and verapamil, may be explained by increased intrahepatocellular substrate availability due to lower hepatic P-glycoprotein activity in women relative to men. Physiological factors resulting in gender-related pharmacokinetic differences include the generally lower bodyweight and organ size, higher percentage of body fat, lower glomerular filtration rate and different gastric motility in women compared with men. Although gender disparity in pharmacokinetics has been identified for numerous drugs, differences are generally only subtle. For a few drugs, e.g. verapamil, beta-blockers and selective serotonin reuptake inhibitors, gender-related differences in pharmacokinetics have been shown to result in different pharmacological responses, but their clinical relevance remains unproven. In contrast, gender differences of clinical importance have clearly been identified for pharmacodynamic processes such as QTc prolongation, and intensive future research efforts are needed to assess the full scope and impact of pharmacodynamic gender disparity on applied pharmacotherapy.
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PMID:How important are gender differences in pharmacokinetics? 1203 91

The HMG-CoA reductase inhibitors (statins) are effective in both the primary and secondary prevention of ischaemic heart disease. As a group, these drugs are well tolerated apart from two uncommon but potentially serious adverse effects: elevation of liver enzymes and skeletal muscle abnormalities, which range from benign myalgias to life-threatening rhabdomyolysis. Adverse effects with statins are frequently associated with drug interactions because of their long-term use in older patients who are likely to be exposed to polypharmacy. The recent withdrawal of cerivastatin as a result of deaths from rhabdomyolysis illustrates the clinical importance of such interactions. Drug interactions involving the statins may have either a pharmacodynamic or pharmacokinetic basis, or both. As these drugs are highly extracted by the liver, displacement interactions are of limited importance. The cytochrome P450 (CYP) enzyme system plays an important part in the metabolism of the statins, leading to clinically relevant interactions with other agents, particularly cyclosporin, erythromycin, itraconazole, ketoconazole and HIV protease inhibitors, that are also metabolised by this enzyme system. An additional complicating feature is that individual statins are metabolised to differing degrees, in some cases producing active metabolites. The CYP3A family metabolises lovastatin, simvastatin, atorvastatin and cerivastatin, whereas CYP2C9 metabolises fluvastatin. Cerivastatin is also metabolised by CYP2C8. Pravastatin is not significantly metabolised by the CYP system. In addition, the statins are substrates for P-glycoprotein, a drug transporter present in the small intestine that may influence their oral bioavailability. In clinical practice, the risk of a serious interaction causing myopathy is enhanced when statin metabolism is markedly inhibited. Thus, rhabdomyolysis has occurred following the coadministration of cyclosporin, a potent CYP3A4 and P-glycoprotein inhibitor, and lovastatin. Itraconazole has been shown to increase exposure to simvastatin and its active metabolite by at least 10-fold. Pharmacodynamically, there is an increased risk of myopathy when statins are coprescribed with fibrates or nicotinic acid. This occurs relatively infrequently, but is particularly associated with the combination of cerivastatin and gemfibrozil. Statins may also alter the concentrations of other drugs, such as warfarin or digoxin, leading to alterations in effect or a requirement for clinical monitoring. Knowledge of the pharmacokinetic properties of the statins should allow the avoidance of the majority of drug interactions. If concurrent therapy with known inhibitors of statin metabolism is necessary, the patient should be monitored for signs and symptoms of myopathy or rhabdomyolysis and the statin should be discontinued if necessary.
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PMID:Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. 1203 92

(R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]- 4-[4-(4-trifluoro-methylphenyl)thiazol-2-yl]benzenesulfonamide (1) is a potent and selective agonist of the human beta3-adrenergic receptor. We report herein the data from studies of the metabolism and excretion of 1 in rats. Five metabolites were identified in the bile of male Sprague-Dawley rats administered 3H-labeled 1 by either oral gavage (10 mg/kg) or intravenous injection (3 mg/kg). These included a pyridine N-oxide derivative (M2), a primary amine resulting from N-dealkylation and loss of the pyridinyl-2-hydroxyethyl group (M4), a carboxylic acid derived from N-dealkylation and loss of the pyridyl-2-hydroxyethyl amine (M5), and the corresponding taurine and isethionic acid conjugates (M1 and M3). Metabolites M1 and M3 also were identified in rats treated with M5 and were generated in incubations of M5 with rat liver subcellular fractions in the presence of ATP and coenzyme A with supplementary taurine or isethionic acid. These results suggest that M5 is the precursor of M1 and M3 and that the formation of these conjugated metabolites follows similar mechanisms of amino acid conjugation. On the other hand, M2, M4, and M5 were produced from 1 in an NADPH-dependent manner in incubations with liver microsomes from rats, dogs, monkeys, and humans. In human liver preparations, these routes of biotransformation were shown to be catalyzed by cytochrome P450 3A4. In a bidirectional transport assay, transport of 1 across a monolayer of cells expressing P-glycoprotein (Pgp) was observed to be similar to that of vinblastine, which is an established substrate of the transporter protein. This finding, together with the observation that the parent compound was excreted in the feces of bile duct-cannulated animals following intravenous dosing, suggests that 1 is subject to Pgp-mediated excretion from intestine of rats.
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PMID:Metabolism of a thiazole benzenesulfonamide derivative, a potent and elective agonist of the human beta3-adrenergic receptor, in rats: identification of a novel isethionic acid conjugate. 1206 36


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