Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 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.
 ...
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

Olanzapine is an "atypical" antipsychotic agent with a high affinity for serotonin 5HT2A/C, 5HT3, 5HT6, and dopamine D1, D2, D3, D4 receptors. Depressed patients with psychotic disorders frequently require treatment with concomitant antipsychotic and antidepressant medications. Imipramine pharmacokinetics serve as a marker for hepatic CYP2D6, CYP1A2, CYP3A activity. An open-label, three-way randomized crossover study was done to determine the safety, pharmacokinetics, and potential for a drug interaction between olanzapine (5 mg) and imipramine (75 mg). Each drug was administered alone and in combination. Nine healthy men, ages 32 to 54 years, enrolled in the study. Psychomotor performance capacities, plasma olanzapine, imipramine, desipramine concentrations, and clinical laboratory tests were measured. Pharmacokinetic variables, vital signs, subjective tests for liveliness, and psychomotor outcomes were analyzed using a two-way ANOVA. Olanzapine was safe. Sedation, postural hypotension, and minor vital sign alterations occurred during all treatments. On the liveliness questionnaire, patients generally reported poorer (less lively) scores with olanzapine alone or coadministered with imipramine versus baseline scores. These effects disappeared within 24 hours after administration. Olanzapine alone and in combination decreased motor-speed tasks (finger tapping and visual-arm random reach) compared with baseline or imipramine treatment. Peak 6-hour changes were statistically significant but clinical importance was only marginal. Olanzapine concentrations were < 19% greater than with imipramine. But olanzapine did not affect the kinetics of imipramine or desipramine and, therefore, did not show a metabolic drug interaction involving CYP2D6.
 ...
PMID:Olanzapine: interaction study with imipramine. 950 89

Lotronex (alosetron hydrochloride) is a 5-HT3 receptor antagonist indicated for the treatment of irritable bowel syndrome (IBS) in females whose predominant bowel habit is diarrhea. Alosetron is extensively metabolized by multiple cytochrome P450 (CYP) enzymes, including CYP2C9 and CYP3A4. Fluoxetine is an antidepressant that is administered as a racemic mixture of equipotent R- and S-enantiomers. Fluoxetine metabolism involves CYP2D6 and CYP2C9 in the formation of its major metabolite, norfluoxetine. This metabolite is also present as two enantiomers, of which only the S-enantiomer exhibits comparable antidepressant activity. This study was conducted to assess the potential for an effect of alosetron on the pharmacokinetics of fluoxetine. This was an open-label, two-period, nonrandomized, crossover study in 12 healthy female and male volunteers. The pharmacokinetics for both enantiomers of fluoxetine and norfluoxetine were examined following single oral doses of 20 mg fluoxetine, given alone and in combination with alosetron 1 mg twice daily for 15 days. The results showed small delays in peak concentration but no clinically significant effect of alosetron on the pharmacokinetics of S- and R-fluoxetine or S- and R-norfluoxetine. Coadministration of alosetron and fluoxetine was well tolerated by all subjects.
 ...
PMID:Effect of alosetron on the pharmacokinetics of fluoxetine. 1130 3

Postoperative nausea and vomiting (PONV) affects approximately one third of patients and may lead to aspiration, dehiscence, esophageal rupture, and increased treatment costs if inadequately controlled. An important therapeutic option for prevention of PONV is 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists. Nonetheless, therapeutic failure sometimes occurs. Metabolism by the cytochrome P450 (CYP) system differs among the 5-HT3 receptor antagonists, and provides a rational explanation for decreased therapeutic efficacy in some patients. Four of the 5-HT3 receptor antagonist agents (dolasetron, ondansetron, palonosetron, and tropisetron) are metabolized in various degrees via CYP2D6, an isoform subject to marked genetic polymorphism. In patients with duplicate CYP2D6 alleles, degradation into inactive metabolites occurs rapidly with these four 5-HT3 receptor antagonists, resulting in decreased efficacy for preventing PONV. Granisetron is the only agent in this class that is not metabolized via CYP2D6. Instead, granisetron is metabolized via the CYP3A4 isoform, which is not subject to significant genetic polymorphism. CYP2D6 genotype screening prior to PONV treatment may allow for modification of antiemetic dosing. An alternative is to use a 5-HT3 agent that is metabolized independently of the CYP2D6 isoform, such as granisetron, that would obviate the need for genotyping and may lead to improved prophylaxis of PONV.
 ...
PMID:Cytochrome P450 2D6 metabolism and 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. 1619 15

5-Hydroxytryptamine (5-HT) receptors are thought to be associated with the gastrointestinal side effects induced by selective serotonin reuptake inhibitors. CytochromeP450 (CYP) 2D6 may also be associated with the side effects induced by fluvoxamine, since the plasma fluvoxamine concentration depends on a CYP2D6 gene polymorphism. This study investigated whether 5-HT receptor and CYP2D6 gene polymorphisms could predict the occurrence of the side effects. The effects of 5-HT receptor and CYP2D6 gene polymorphisms on the incidence of gastrointestinal side effects induced by fluvoxamine were investigated in 100 depressed outpatients who gave written consent to participate in the study. The patients visited every 2 weeks until the week 12 end point and the fluvoxamine dose was changed in response to their clinical symptoms. All side effects, including the gastrointestinal side effects, were assessed at each visit. Polymerase chain reaction was used to determine A-1438G of the 5-HT2A receptor, C195T and Pro16Ser of the 5-HT3A receptor, Tyr129Ser of the 5-HT3B receptor, and the *5 and *10 alleles of CYP2D6. Both the A-1438G polymorphism of the 5-HT2A receptor gene and the CYP2D6 gene polymorphism had significant effects on the incidence of gastrointestinal side effects. Cox regression was used to analyze the combination effect of the two polymorphisms on the gastrointestinal side effects. Cox regression analysis showed that lower metabolizers (LMs) of CYP2D6 with the G/G genotype of the 5-HT2A A-1438G polymorphism had a 4.242-fold (P = 0.009) and LMs with the A/G genotype had a 4.147-fold (P = 0.004) higher risk of developing gastrointestinal side effects than normal metabolizers with the A/A genotype. The 5-HT3A and 3B gene polymorphisms had no significant effects on the incidence of gastrointestinal side effects. 5-HT2A receptor and CYP2D6 gene polymorphisms had a synergistic effect for the prediction of fluvoxamine-induced gastrointestinal side effects.
 ...
PMID:Polymorphisms in the 5-hydroxytryptamine 2A receptor and CytochromeP4502D6 genes synergistically predict fluvoxamine-induced side effects in japanese depressed patients. 1620 77

Nausea and vomiting are 2 of the most upsetting adverse reactions of chemotherapy. Current guidelines propose 5-hydroxytryptamine3 (5-HT3) receptor antagonists as a pharmacologic intervention for acute and delayed nausea and vomiting [chemotherapy-induced nausea and vomiting (CINV)] associated with moderately and highly emetogenic chemotherapy. Meanwhile, both postoperative nausea and vomiting (PONV) and postdischarge nausea and vomiting are challenging situations after surgeries and procedures. Prophylactic and therapeutic combinations of antiemetics are recommended in patients at high risk of suffering from PONV and postdischarge nausea and vomiting. Granisetron (Kytril) is a selective 5-HT3 receptor antagonist that does not induce or inhibit the hepatic cytochrome P-450 system in vitro. There are also 4 other antagonists of 5-HT3 receptor (dolasetron, ondansetron, palonosetron, and tropisetron) being metabolized via the CYP2D6 and are subject to potential genetic polymorphism. The launch of a new class of antiemetics, the substance P/neurokinin1 receptor antagonists, was attributed to the scientific update on the central generator responsible for emesis and role of substance P. There has been mounting interest in exploring integrative medicine, either acupuncture or acustimulation of P6 (Nei-Kuwan), to complement the western medicine for prevention and management of nausea and vomiting. The potential application of cannabinoids, either alone or in combination with other agents of different mechanism, could contribute further to improve outcome in CINV. Implementation of future treatment guidelines for more effective management of CINV and PONV could certainly improve the efficacy and outcome of cancer and postoperative care.
 ...
PMID:A review of granisetron, 5-hydroxytryptamine3 receptor antagonists, and other antiemetics. 2084 45