Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dolasetron mesilate [(2 alpha, 6 alpha, 8 alpha, 9a beta)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl-1H-indole-3-c arboxylate monomethane-sulfonate], is a 5-HT3 receptor antagonist, which is in development for the treatment of chemotherapy-induced emesis. The compound is rapidly reduced by carbonyl reductase to form its major pharmacologically active metabolite reduced dolasetron (red-dolasetron), which us further metabolized by cytochrome P450 (CYP450). Studies were conducted, using human liver microsomes, to characterize the CYP450 enzymes responsible for the in vitro metabolism of red-dolasetron. Red-dolasetron underwent oxidation of the indole aromatic ring at positions 5, 6, and 7, and also N-oxidation. Enzyme-selective inhibition and correlation studies showed that hydroxylation of red-dolasetron was CYP2D6-dependent, and N-oxidation was conducted by CYP3A4. The rate of formation of 6-hydroxy red-dolasetron was significantly correlated with that of 5-hydroxy red-dolasetron, which further suggested that these metabolites were formed by the same CYP450 enzyme(s). Inhibition studies also demonstrated that 6-hydroxylation was, to a lesser extent, CYP3A4-dependent. This was confirmed by correlation experiments, wherein formation of this metabolite was significantly correlated with that of N-oxide formation, in quinidine-inhibited microsomes. Results were compared with those obtained with two other indole-containing 5-HT3 receptor antagonists: tropisetron and ondansetron. Tropisetron hydroxylation was CYP2D6-dependent, whereas that of ondansetron was both CYP2D6- and CYP2E1-dependent. Results were further confirmed, when compounds were incubated with microsomes containing recombinant human liver CYP2D6, CYP3A4, and CYP2E1. Red-dolasetron was a competitive inhibitor of CYP2D6, with an IC50 value of 70 microM, which is 2 orders of magnitude above maximum plasma concentrations found in humans. The implications of these in vitro results to the in vivo metabolism of these compounds in humans and their potential pharmacokinetic consequences is discussed.
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PMID:Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of dolasetron. Comparison with other indole-containing 5-HT3 antagonists. 872 43

Ritonavir (RTV), a protease inhibitor, and carbamazepine (CBZ), an anticonvulsant, were administered concurrently to a patient who had human immunodeficiency virus infection and epilepsy. The combination resulted in elevated serum concentrations of CBZ, with accompanying vomiting, vertigo, and transient liver dysfunction. After discontinuing RTV and reducing the dosage of CBZ, the serum concentration of CBZ returned to the optimal range, symptoms subsided, and liver function returned to baseline. Carbamazepine is metabolized in the liver to a large extent by the cytochrome P450 (CYP) system, especially CYP3A4, 2C8, and 1A2, whereas RTV is metabolized primarily by CYP3A and is a potent inhibitor of this enzyme. Careful clinical monitoring may help prevent adverse drug interactions when these drugs are administered concurrently.
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PMID:Potential interaction between ritonavir and carbamazepine. 1090 77

Exatecan mesylate (DX-8951f) is a new hexacyclic camptothecin analogue with favorable attributes compared to topotecan and CPT-11, including watersolubility, greater potency against topoisomerase I, lack of esterase-dependent activation, broad antitumor activity, and low cross-resistance against MDR-1 overexpressing tumors. In preclinical studies, the compound demonstrated a favorable toxicology profile with hematologic dose-limiting toxicity and moderate gastrointestinal toxicity, linear pharmacokinetics, P450 hepatic metabolism (CYP3A4 and CYP1A2), and predominately fecal excretion. The results of six U.S. and European phase I clinical trials as well as two Japanese studies are presented including total DX-8951 and lactone DX-8951 pharmacokinetics. The toxicity profile was similar for all schedules of administration. Hematologic toxicity was dose-dependent and reversible. Neutropenia was dose-limiting in minimally pretreated patients, whereas neutropenia and thrombocytopenia were dose-limiting in heavily pretreated patients. Non-hematologic toxicity included moderate gastrointestinal toxicity (nausea, vomiting > diarrhea), transient elevation of hepatic transaminases, asthenia, and alopecia. Two cases of acute pancreatitis not predicted by preclinical toxicology were also observed. Antineoplastic activity was detected in several solid tumor types: non-small cell lung cancer, extrapulmonary small cell cancer, colorectal cancer, hepatocellular cancer, and sarcoma. Antitumor activity was seen in CPT-11 and topotecan-resistant tumors. Pharmacokinetics were linear within the dose range tested. A pharmacokinetic/pharmacodynamic model predictive of DX-8951f-induced neutropenia in individual patients was developed. The daily x5, every 3-week schedule with the drug administered as a 30-minute intravenous infusion was selected for future phase II clinical trials based on its superior antitumor activity.
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PMID:DX-8951f: summary of phase I clinical trials. 1119 1

LC-NMR was applied to identify the polar volatile metabolite of MK-0869. MK-0869, a morpholine-based compound containing a triazolone ring, is a very potent NK(1) receptor antagonist. Currently, it is in development as an anti-emesis agent in chemotherapy treatments. The primary metabolites of MK-0869, M1 and M2, are non-polar and lack the triazolone ring. Incubation of [14C]M1 with liver microsomes from male rats produced a very polar and volatile metabolite, M3. Analysis was not possible by LC-MS or by conventional NMR because of poor ionization, small molecular weight and volatility, leaving chemical derivatization and LC-NMR as alternative methods. Reduction of M3 with NaBH(4) resulted in a derivative that had the same retention time as p-fluorophenylethylene glycol on HPLC. A small aliquot of the solution containing M3 was passed through the LC of the LC-NMR system, which was connected on-line with a radioactivity detector. The simultaneous UV and radioactivity chromatograms thus identified the chromatographic UV peak that was associated with the metabolite. Analysis was carried out by stop-flow on another portion of this fraction. From the chemical derivatization and the analysis by LC-NMR, M3 is shown to be p-fluoro-alpha-hydroxyacetophenone. Further studies using LC-NMR showed that M3 could be generated from both M1 and M2 in NADPH-dependant reactions catalyzed by microsomes containing recombinant human CYP2C19, CYP1A2 or CYP3A4.
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PMID:Application of LC-NMR for the study of the volatile metabolite of MK-0869, a substance P receptor antagonist. 1246 14

Aprepitant is an oral neurokinin-1 receptor antagonist which acts centrally to block chemotherapy-induced emesis. Its main pathway of elimination is by the cytochrome p450 isozyme CYP3A4, which is the basis for drug interactions with dexamethasone and oral contraceptives. Aprepitant is well tolerated, and phase II trials in high-dose cisplatin-induced emesis showed that it is most effective when 125 mg orally is added to a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone for acute emesis and then an 80 mg oral dose continued with dexamethasone on days 2 and 3 to prevent delayed emesis. Two pivotal phase III trials enrolling a total of 1099 patients showed that the complete control of emesis improved by 20% in patients receiving aprepitant as compared with standard therapy, with the most impressive differences being in delayed emesis. Control was maintained over multiple cycles and occurred in both males and females and young and old adults.
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PMID:Aprepitant in antiemetic combinations to prevent chemotherapy-induced nausea and vomiting. 1505 69

(1) Platinum-based chemotherapy is generally used to treat advanced-stage non small-cell lung cancer (stages III and IV), but has only a modest impact on survival. There is no reference treatment. (2) Gefitinib inhibits the tyrosine kinase activity of the receptor for EGF (epidermal growth factor), which is thought to be involved in tumour growth. It has a temporary licence in France and is used on a named-patient basis, but full marketing authorisation has already been granted in Japan, the United States, and elsewhere. (3) Two double-blind dose-finding studies compared two doses of oral gefitinib monotherapy (250 mg/day and 500 mg/day) in patients in whom at least two lines of chemotherapy had failed. The results were favourable, with a median survival of 6 months and a symptomatic improvement in some patients, but they are undermined by the absence of a placebo group and by major protocol violations. (4) Two double-blind trials, each in more than 1000 patients, showed that gefitinib does not increase the efficacy of first-line platinum combinations. (5) About 15% of patients receiving gefitinib monotherapy in clinical trials stopped taking the treatment because of adverse events. The most frequent were gastrointestinal (diarrhea, nausea, vomiting) and cutaneous (rash, acne, dry skin, pruritus). (6) Interstitial pneumonitis occurred in about 1% of patients, and was fatal in about one-third of cases. (7) Gefitinib is metabolised by the cytochrome P450 isoenzyme CYP3A4, so carries a potentially high risk of interactions. (8) In practice, more thorough assessment of gefitinib is needed to determine whether this new drug is beneficial for patients with non small-cell lung cancer. Marketing authorisation is not currently justified.
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PMID:Gefitinib: new preparation. Non small-cell lung cancer: stricter assessment needed. 1549 96

Atazanavir is the first once-daily protease inhibitor for the treatment of human immunodeficiency virus type 1 infection and should be used only in combination therapy, as part of a highly active antiretroviral therapy (HAART) regimen. In addition to being the most potent protease inhibitor in vitro, atazanavir has a distinct cross-resistance profile that does not confer resistance to other protease inhibitors. However, resistance to other protease inhibitors often confers clinically relevant resistance to atazanavir. Currently, atazanavir is not a preferred protease inhibitor for initial HAART regimens. In treatment-naive patients, atazanavir can be given as 400 mg/day. However, atazanavir should be pharmacologically boosted with ritonavir in treatment-experienced patients or when coadministered with either tenofovir or efavirenz. Patients who receive atazanavir experience similar rates of adverse events compared with patients receiving comparator regimens. An exception is an increased risk of asymptomatic hyperbilirubinemia, which is due to competitive inhibition of uridine diphosphate-glucuronosyltransferase 1A1. Although hyperbilirubinemia is a common adverse drug reaction of atazanavir therapy (22-47%), fewer than 2% of patients discontinue atazanavir therapy because of this adverse effect. Common adverse effects reported with atazanavir include infection, nausea, vomiting, diarrhea, abdominal pain, headache, peripheral neuropathy, and rash. Of significance, fewer abnormalities have been observed in plasma lipid profiles in patients treated with atazanavir compared with other protease inhibitor-containing regimens. As with other protease inhibitors, atazanavir is also a substrate and moderate inhibitor of the cytochrome P450 (CYP) system, in particular CYP3A4 and CYP2C9. Clinically significant drug interactions include (but are not limited to) antacids, proton pump inhibitors, histamine type 2 receptor antagonists, tenofovir, diltiazem, irinotecan, simvastatin, lovastatin, St. John's wort, and warfarin. We conclude that atazanavir is a distinctively characteristic protease inhibitor owing to its in vitro potency, once-daily dosing, distinct initial resistance pattern, and infrequent association with metabolic abnormalities.
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PMID:Atazanavir for the treatment of human immunodeficiency virus infection. 1558 41

Aprepitant, a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors, is the active ingredient of EMEND which has recently been approved by the FDA for the prevention of chemotherapy-induced nausea and vomiting (CINV). Aprepitant undergoes extensive metabolism, primarily via CYP3A4 mediated oxidation. It is eliminated primarily by metabolism and is not renally excreted. The apparent terminal half-life in humans ranged from 9 to 13 hours. Early development studies led to the development of a nanoparticle formulation to enhance exposure and minimize food effects. Two large randomized trials accruing 1099 patients studied the effect in patients receiving cisplatin of adding aprepitant to ondansetron and dexamethasone on day 1 then to dexamethasone on days 2 and 3 to control delayed emesis. The complete response of no vomiting and no rescue medication overall from days 1 to 5 improved from 48% to 68% (p<0.001), a 13% improvement in acute emesis but a 21% improvement in delayed emesis with the improvement from 51% to 72% (p<0.001). Similarly, 866 patients treated with cyclophosphamide plus either doxorubicin or epirubicin, received either ondansetron, dexamethasone, and aprepitant on day 1 followed by aprepitant on days 2 and 3 or ondansetron and dexamethasone on day 1 and dexamethasone on days 2 and 3. The overall complete response rate over 5 days was better for the aprepitant group 50.8% vs 42.5% (p=0.015). Complete responses were reported in more patients taking aprepitant in both the acute (76% vs 69%, p=0.034) and delayed (55% vs 49%, p=0.064) phases of vomiting. There were no clinically relevant differences in toxicity by adding aprepitant and improvements in the quality of life of patients on chemotherapy were recorded.
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PMID:Nanomedicines in the treatment of emesis during chemotherapy: focus on aprepitant. 1772 7

Aprepitant (Emend, Merck Inc., Whitehouse Station, NJ), a neurokin-1 (NK1) receptor antagonist, is a first-in-class agent approved for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). It competitively binds to NK1 receptors, blocks the binding of substance P, the natural ligand, and prevents signal transduction. Early clinical trials showed that aprepitant combined with standard therapy (corticosteroids and serotonin receptor antagonists) provided improved antiemetic protection in patients receiving highly emetogenic chemotherapy. The results of three randomized, double blind, placebo-controlled trialsthat compared aprepitant plus standard therapy with standard therapy plus placebo showed significant improvements in complete response rates (defined as no emesis and no use of rescue medication) with the addition of aprepitant (58.8% to 71% vs. 43.3% to 52.3%; P < .05 for all). Benefits were found in the acute phases, delayed phases, and in the overall study periods. Multiple secondary endpoints also favored the addition of aprepitant, particularly in the delayed phases and overall study periods. In extended trials in which treatment was continued for up to 6 cycles of highly emetogenic chemotherapy, the antiemetic effect was maintained and remained statistically greater for the aprepitant plus standard therapy group compared with standard therapy and placebo. The addition of aprepitant was well tolerated, and common adverse events were similar to those seen with standard therapy plus placebo. A clinically significant drug interaction with CYP3A4-metabolized cytotoxic agents was reported in one trial, but not confirmed in the others. The additional protection confirmed by aprepitant translated into a decreased impact of CINV on patients' daily lives as measured by the Functional Living Index-Emesis questionnaire. Aprepitant adds additional antiemetic protection to standard therapy and should be considered in all patients receiving highly emetogenic chemotherapy.
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PMID:Antiemetic studies on the NK1 receptor antagonist aprepitant. 1978 Feb 56

Yahom Ampanthong, a Thai traditional medicine, is commonly used for treatment of nausea, vomiting and syncope. Its formula is composed of more than 10 medicinal plants. Currently, the herbal-drug interactions were reported among the case of co-administration of traditional and Western medicines, since cytochrome P450 enzymes involve in drug metabolism and affect the drug action. This study aimed to investigate the effects of Yahom extracts on hepatic cytochrome P450 enzymes and pentobarbital-induced sleeping in mice. Powder of Yahom Ampanthong was extracted with three different solvents, i.e., dichloromethane, methanol and distilled water. The activities of CYP1A1, CYP1A2, CYP2B, CYP2E1 and CYP3A4 were determined after the administration of Yahom extracts for 4 weeks. All three extracts significantly inhibited CYP1A1, CYP1A2, CYP2E1 activities. In contrast, only dichloromethane and methanol extracts enhanced CYP2B activity. However, all three extracts did not affect CYP3A4 activity. When compared to the control group, the dichloromethane extract-treated animals showed shorter pentobarbital-induced sleeping time after treatment for 1 and 4 weeks. In conclusion, Yahom Ampanthong extracts modulated hepatic microsomal cytochrome P450 activities and decreased the pentobarbital-induced sleeping time. Therefore, the concomitant administration of Yahom with certain drugs may give rise to the herbal-drug interaction, which may affect the clinical implication of drug actions.
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PMID:Interference of Thai traditional medicine (Yahom Ampanthong) on hepatic cytochrome P450 enzymes and pentobarbital-induced sleeping in mice. 2191 58


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