Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The new 5-hydroxytryptamine type 3 (5HT3) receptor antagonist tropisetron is used in the treatment of chemotherapy-related nausea. The drug is extensively metabolized in man, with the enzymes involved in tropisetron biotransformation being unknown. Identification of these enzymes would make it possible to predict both interindividual variability in plasma concentrations and metabolic interaction potential. The present in vitro study was therefore aimed at identifying and characterizing the cytochrome P450 enzymes catalysing tropisetron metabolism. Enzyme kinetics for formation of 5-hydroxy (5-OH-ICS), 6-hydroxy (6-OH-ICS) and N-demethyl tropisetron (N-De-ICS) were studied in the microsomal fraction of eight human livers (seven livers from extensive metabolizer (EM), one liver from a poor metabolizer (PM) for CYP2D6). Formation of 5-OH-ICS and 6-OH-ICS was biphasic with a high (5-OH: Km 3.9 +/- 2.1 microM; Vmax 1.88 +/- 0.73 pmol/mg/min; 6-OH: Km 4.66 +/- 1.84 microM; Vmax 4.00 +/- 1.77 pmol/mg/min) and low (5-OH: Km 172 +/- 51 microM; Vmax 17.0 +/- 9.4 pmol/mg/min; 6-OH: Km 266.0 +/- 76.0 microM; Vmax 81.4 +/- 27.9 pmol/mg/min) affinity component. The high-affinity component was identified as CYP2D6 which exhibits a genetic polymorphism in man. This component was absent in the PM liver. The low-affinity component was present in EM and PM livers and was identified as CYP3A4. LKM1 antibodies directed against CYP2D6 completely inhibited the high affinity component. Quinidine (0.5 microM) inhibited 5- and 6-hydroxylation at 10-80 microM tropisetron concentrations competitively by 70% with Ki values of 10 and 18 nM, respectively. Stably-expressed CYP2D6 catalysed the formation of both 5-OH-ICS and 6-OH-ICS. Both inhibition experiments and use of stably-expressed enzymes revealed formation of N-De-ICS to be mediated by CYP3A4. Based on in vitro intrinsic clearances CYP2D6-catalysed 5-OH-ICS and 6-OH-ICS is the predominant route of tropisetron elimination. Large phenotype-related differences in total clearance are to be expected after administration of tropisetron. However, in view of the wide therapeutic index of tropisetrone and the rather high Ki for inhibition of the metabolism of other drugs by tropisetron, both the interindividual variability and the interaction potential appear to be of no clinical relevance.
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PMID:In vitro characterization of cytochrome P450 catalysed metabolism of the antiemetic tropisetron. 759 39

Paroxetine is a trans-isomeric phenylpiperidine with antidepressant properties induced by selective inhibition of the neuronal high affinity uptake of serotonin. In comparison with other selective serotonin uptake inhibitors paroxetine is 2 to 23 times more potent. With the exception of a low affinity to muscarinic receptors, which is not relevant for therapeutic effects, it does not interact directly with monoamine neurotransmitter receptors. Paroxetine is applied orally at single daily doses of 20 to 50 mg and well absorbed from the gastrointestinal tract. It undergoes a partially saturated first pass metabolism which reduces the bioavailability at therapeutic doses to about 30-60%. Maximal blood levels are reached 2 to 8 hours after oral administration. In the plasma 95% of the drug are bound to protein. Paroxetine is eliminated after transformation in the liver into pharmacologically inactive metabolites. High affinity to the cytochrome P450 isoenzyme CYP2D6 indicates that interferences occur with other drugs which are metabolized via the same isoenzyme. Although clinical practice has not reported problematic drug interactions so far, comedications with tricyclic antidepressants should be avoided. The most frequent side effects of paroxetine concern nausea and somnolescence. Since cardiotoxicity or other toxic side effects are much less frequent than under tricyclic antidepressants paroxetine seems advantageous in elderly patients. The onset of antidepressant effects requires several weeks as known for all currently available antidepressants. The pharmacokinetic and pharmacodynamic properties of paroxetine taken together indicate that this selective serotonin uptake inhibitor seems advantageous to other antidepressant agents because of its high selectivity and poor toxicity.
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PMID:[Paroxetine: pharmacokinetics and pharmacodynamics]. 795 22

The pharmacokinetics of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) with antidepressant properties, are well established. After oral administration, the drug is almost completely absorbed from the gastrointestinal tract, and the extent of absorption is unaffected by the presence of food. Despite complete absorption, oral bioavailability in man is approximately 50% on account of first-pass hepatic metabolism. Peak plasma fluvoxamine concentrations are reached 4 to 12 hours (enteric-coated tablets) or 2 to 8 hours (capsules, film-coated tablets) after administration. Steady-state plasma concentrations are achieved within 5 to 10 days after initiation of therapy and are 30 to 50% higher than those predicted from single dose data. Fluvoxamine displays nonlinear steady-state pharmacokinetics over the therapeutic dose range, with disproportionally higher plasma concentrations with higher dosages. Plasma fluvoxamine concentrations show no clear relationship with antidepressant response or severity of adverse effects. Fluvoxamine undergoes extensive oxidative metabolism, most probably in the liver. Nine metabolites have been identified, none of which are known to be pharmacologically active. The specific cytochrome P450 (CYP) isoenzymes involved in the metabolism of fluvoxamine are unknown. CYP2D6, which is crucially involved in the metabolism of paroxetine and fluoxetine, appears to play a clinically insignificant role in the metabolism of fluvoxamine. The drug is excreted in the urine, predominantly as metabolites, with only negligible amounts ( < 4%) of the parent compound. Fluvoxamine shows a biphasic pattern of elimination with a mean terminal elimination half-life of 12 to 15 hours after a single oral dose; this is prolonged by 30 to 50% at steady-state. Plasma protein binding of fluvoxamine (77%) is low compared with that of other SSRIs. Fluvoxamine pharmacokinetics are substantially unaltered by increased age or renal impairment. However, its elimination is prolonged in patients with hepatic cirrhosis. Fluvoxamine inhibits oxidative drug metabolising enzymes (particularly CYP1A2, and less potently and much less potently CYP3A4 and CYP2D6, respectively) and has the potential for clinically significant drug interactions. Drugs whose metabolic elimination is impaired by fluvoxamine include tricyclic antidepressants (tertiary, but not secondary, amines), alprazolam, bromazepam, diazepam, theophylline, propranolol, warfarin and, possibly, carbamazepine. Fluvoxamine is a second generation antidepressant that selectively inhibits neuronal reuptake of serotonin (5-hydroxytryptamine; 5-HT). Fluvoxamine exhibits antidepressant activity similar to that of the tricyclic antidepressants, but has a somewhat improved tolerability profile, particularly with respect to a lower incidence of anticholinergic effects and reduced cardiotoxic potential. However, gastrointestinal adverse effects, especially nausea, are seen more frequently with fluvoxamine than with the tricyclic antidepressants. Fluvoxamine does not have an asymmetric carbon in its structure (fig. 1) and therefore does not exist as optical isomers. For this reason, the potentially confounding problem of stereoisomerism does not arise with fluvoxamine.
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PMID:Overview of the pharmacokinetics of fluvoxamine. 884 17

The effect of comedication with fluvoxamine on the plasma concentrations of the enantiomers of citalopram and its metabolites in dextromethorphan/mephenytoin phenotyped patients pretreated with citalopram (CIT) was studied: seven female patients (45.1 +/- 13.9 years) suffering from a major depressive episode [ICD-10: F32.2 (n = 3 patients), F33.2 (n = 2), F32.10 (n = 1) or F32.11 (n = 1)], who were non-responders to a 3-week treatment with 40 mg/day CIT (From day-21 to day 0) (day 0: MADRS score > or = 12), were co-medicated for another 3 weeks with fluvoxamine (50 mg/day from day 1-7, 100 mg/day from day 14-21). All patients were extensive metabolizers of mephenytoin (CYP2C19) and dextromethorphan (CYP2D6), except one patient, who had a genetic deficiency of CYP2D6. There was a significant increase of the plasma concentrations of S- and R-citalopram from day 0 (27 +/- 14 micrograms/l and 55 +/- 23 micrograms/l, respectively) to day 21 (83 +/- 38 micrograms/l and 98 +/- 44 micrograms/l, respectively), after addition of fluvoxamine (P < 0.02, for each comparison), and the mean ratio S/R-citalopram increased from 0.48 to 0.84. S-Citalopram inhibits more potently 5-HT uptake than R-citalopram: therefore, fluvoxamine increases the pharmacologically more active S-citalopram with some stereoselectivity. According to a previous in vitro study, this pharmacokinetic interaction occurs on the level of CYP2C19, but also of CYP2D6 and CYP3A4 which, in contrast to CYP1A2, contribute to the N-demethylation of citalopram and which are stereoselectively inhibited by fluvoxamine. All but one patient showed clinical improvement by a decrease of the MADRS score by at least 50% and a final score < or = 13 (mean +/- SD: day 0:30.6 +/- 9.2; day 21:11.0 +/- 6.5). Some patients showed minor symptoms, such as nausea and tremor, but the combined treatment was generally well tolerated.
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PMID:Non-response to citalopram in depressive patients: pharmacokinetic and clinical consequences of a fluvoxamine augmentation. 898 13

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

Moclobemide is a reversible inhibitor of monoamine-oxidase-A (RIMA) and has been extensively evaluated in the treatment of a wide spectrum of depressive disorders and less extensively studied in anxiety disorders. Nearly all meta-analyses and most comparative studies indicated that in the acute management of depression this drug is more efficacious than placebo and as efficacious as tricyclic (or some heterocyclic) antidepressants or selective serotonin reuptake inhibitors (SSRIs). There is a growing evidence that moclobemide is not inferior to other antidepressants in the treatment of subtypes of depression, such as dysthymia, endogenous (unipolar and bipolar), reactive, atypical, agitated, and retarded depression as with other antidepressants limited evidence suggests that moclobemide has consistent long-term efficacy. However, more controlled studies addressing this issue are needed. For patients with bipolar depression the risk of developing mania seems to be not higher with moclobemide than with other antidepressants. The effective therapeutic dose range for moclobemide in most acute phase trials was 300 to 600 mg, divided in 2 to 3 doses. While one controlled trial and one long-term open-label study found moclobemide to be efficacious in social phobia, three controlled trials subsequently revealed either no effect or less robust effects with the tendency of higher doses (600 - 900 mg/d) to be more efficacious. Two comparative trials demonstrated moclobemide to be as efficacious as fluoxetine or clomipramine in patients suffering from panic disorder. Placebo-controlled trials in this indication are, however, still lacking. A relationship between the plasma concentration of moclobemide and its therapeutic efficacy is not apparent but a positive correlation with adverse events has been found. Dizziness, nausea and insomnia occurred more frequently on moclobemide than on placebo. Due to negligible anticholinergic and antihistaminic actions, moclobemide has been better tolerated than tri- or heterocyclic antidepressants. Gastrointestinal side effects and, especially, sexual dysfunction were much less frequent with moclobemide than with SSRIs. Unlike irreversible MAO-inhibitors, moclobemide has a negligible propensity to induce hypertensive crisis after ingestion of tyramine-rich food ("cheese-reaction"). Therefore, dietary restrictions are not as strict. However, with moclobemide doses above 900 mg/d the risk of interaction with ingested tyramine might become clinically relevant. After multiple dosing the oral bioavailability of moclobemide reaches almost 100%. At therapeutic doses, moclobemide lacks significant negative effects on psychomotor performance, cognitive function or cardiovascular system. Due to the relative freedom from these side effects, moclobemide is particularly attractive in the treatment of elderly patients. Moclobemide is a substrate of CYP2C19. Although it acts as an inhibitor of CYP1A2, CYP2C19, and CYP2D6, relatively few clinically important drug interactions involving moclobemide have been reported. It is relatively safe even in overdose. The drug has a short plasma elimination half-life that allows switching to an alternative agent within 24 h. Since it is well tolerated, therapeutic doses can often be reached rapidly upon onset of treatment. Steady-state plasma levels are reached approximately at one week following dose adjustment. Patients with renal dysfunction require no dose reduction in contrast to patients with severe hepatic impairment. Cases of refractory depression might improve with a combination of moclobemide with other antidepressants, such as clomipramine or a SSRI. Since this combination has rarely been associated with a potentially lethal serotonin syndrome, it requires lower entry doses, a slower dose titration and a more careful monitoring of patients. Combination therapy with moclobemide and other serotonergic agents, or opioids, should be undertaken with caution, although no serious adverse events have been published with therapeutic doses of moclobemide to date. On the basis of animal data the combined use of moclobemide with pethidine or dextropropoxyphene should be avoided. There is no evidence that moclobemide would increase body weight or produce seizures. Some preclinical data suggest that moclobemide may have anticonvulsant property.
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PMID:Moclobemide: therapeutic use and clinical studies. 1504 13

Drugs with long terminal half-lives, such as terbinafine, have a potential for involvement in both long-lasting drug-drug interactions and interactions appearing weeks after discontinuation. We present a case report on a 37-year-old white woman with normal CYP2D6 metabolic capacity who was treated with amitriptyline, valproate, and olanzapine when terbinafine was introduced. Shortly thereafter she experienced extreme dryness of the mouth, nausea, and dizziness accompanied by a large increase in the serum concentrations of amitriptyline and nortriptyline. Terbinafine therapy was discontinued, and the amitriptyline dose was reduced. Surprisingly, the serum concentrations of amitriptyline and nortriptyline did not return to baseline until approximately 6 months later. Studies have shown that terbinafine is a highly potent competitive inhibitor of CYP2D6. CYP2D6 is an important intermediate enzyme in metabolism of amitriptyline to nortriptyline. Nortriptyline is further metabolized to 10-hydroxy metabolites, mainly by CYP2D6. It is, therefore, likely that the concomitant use of terbinafine was the major cause of the increased serum concentrations of amitriptyline and nortriptyline. Very different terbinafine elimination half-lives (17-400 hours) are stated in the physicians' reference guides. If the shortest estimates are used when adjusting the dose of interacting drugs, the risk of underestimating the duration of the interaction is large. Based on our data there is a risk of clinically significant drug-drug interactions for at least 3 months after stopping terbinafine intake.
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PMID:Prolonged pharmacokinetic drug interaction between terbinafine and amitriptyline. 1617 44

We investigated the effect of 5-hydroxytryptamine 3A and 3B receptor (HTR3A and HTR3B) gene polymorphisms on nausea induced by paroxetine in Japanese psychiatric patients. Blood samples were collected from 78 individuals after at least 2 weeks treatment with the same daily dose of paroxetine. The patients visited every 2 weeks and the paroxetine dose was changed in response to their clinical symptoms. Nausea was assessed at each visit. The Tyr129Ser polymorphism of the HTR3B gene had a significant effect on the incidence of nausea (P=0.038). Logistic regression analysis also showed that patients with the Tyr/Tyr genotype had a 3.95-fold (P=0.048) higher risk of developing nausea than patients with the Ser allele. HTR3A gene polymorphisms and the CYP2D6 gene polymorphisms had no significant effect on the incidence of nausea. The mean score of nausea severity was corrected by the Bonferroni test. HTR3B gene polymorphisms are significant predictors of paroxetine-induced nausea.
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PMID:The effect of 5-hydroxytryptamine 3A and 3B receptor genes on nausea induced by paroxetine. 1653 7

Tramadol, a centrally acting analgesic, consists of two enantiomers, both of which contribute to analgesic activity via different mechanisms. (+) Tramadol and the metabolite (+) -O- desmethyl-tramadol (M1) are agonists of the mu opioid receptor. (+) Tramadol also stimulates presinaptic release of serotonin and inhibits serotonin reuptake whereas (-) tramadol inhibits norepinephrine reuptake. Thus tramadol enhances inhibitory effects on pain transmission both by opioid and monoaminergic mechanisms. The complementary and synergistic actions of the two enantiomers improve the analgesic efficacy and tolerability profile of the racemate. Following oral administration the bioavailability of tramadol is high and with new slow release preparations twice daily administration enables effective pain control. The recommended maximum daily dose of tramadol is 400 mg/day. Tramadol is characterised by low plasma protein binding and quite extensive tissue distribution. Elimination is primarily by the hepatic route (metabolism by CYP2D6) and partly by the renal route. It is effective in different types of moderate-to-severe acute and chronic pain, including neuropathic pain, low back pain, osteoarthritis pain and breakthrough pain. It also causes fewer opioid-type adverse effects, e.g. nausea, drowsiness, vomiting, dry mouth and constipation. Although trials in literature demonstrate immune-stimulating effects of tramadol, there are also trials suggesting immunesuppressive effects that are lesser than morphine. Owing to its pharmacological properties, tramadol is more appropriate than NSAIDs for patients suffering from gastrointestinal and renal problems. Besides its proven clinical efficacy tramadol is a safe drug as respiratory depression, cardiovascular side effects, drug abuse and dependence are of minor clinical relevance, unlike some other opioids.
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PMID:[An atypical opioid analgesic: tramadol]. 1678 63

Selective serotonin reuptake inhibitor (SSRI)-induced nausea can be severe enough to lead to early treatment discontinuation. However, it is currently not possible to predict the occurrence of nausea before the initiation of SSRI treatment. In this study, we investigated the effect of genetic polymorphisms in the 5-hydroxytryptamine type 2A, 3A, and 3B (5-HT3B) receptors, 5-HT transporter, and CYP2D6 genes on the incidence of paroxetine-induced nausea. A consecutive series of 72 Japanese patients with depressive or anxiety disorders were treated with paroxetine. Paroxetine-induced nausea was assessed by a pharmacist and was observed in 29.2% of the patients. A significant (nominal p=0.00286) association was found between the incidence of nausea and the -100_-102AAG insertion/deletion polymorphism of the 5-HT3B receptor gene. No significant associations were observed between the other genetic polymorphisms and the incidence of nausea. The -100_-102AAG deletion variant of the 5-HT3B receptor gene may affect paroxetine-induced nausea.
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PMID:Genetic polymorphisms in the 5-hydroxytryptamine type 3B receptor gene and paroxetine-induced nausea. 1769 94


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