Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Administration of the antineoplastic doxorubicin to rodents causes depression of hepatic cytochrome P450 (CYP) dependent biotransformation, an effect that has been partially attributed to the ability of doxorubicin to stimulate microsomal lipid peroxidation. Since doxorubicin can be bioactivated by the CYP/NADPH-CYP reductase system to products that bind covalently to microsomal protein, we hypothesized that doxorubicin functions as a mechanism-based inactivator of hepatic microsomal CYPs and (or) NADPH-CYP reductase under conditions in which doxorubicin-stimulated NADPH-dependent lipid peroxidation is minimized. In vitro studies were conducted with hepatic microsomes isolated from untreated and phenobarbital-treated male rats. Unlike the positive control carbon tetrachloride, doxorubicin (10 microM) did not stimulate NADPH-dependent lipid peroxidation in microsomal incubations containing EDTA (1.5 mM). Doxorubicin did not cause NADPH-dependent loss of microsomal CYP, heme, or steroid hydroxylation activities selective for CYP2A, CYP2B, CYP2C11, and CYP3A. The positive control 1-aminobenzotriazole caused marked NADPH-dependent decreases in all of these parameters. Neither doxorubicin nor 1-aminobenzotriazole caused NADPH-dependent loss of NADPH-CYP reductase activity, and neither compound altered the immunoreactive protein levels of CYP2B, CYP2C11, CYP3A, and NADPH-CYP reductase. These results indicate that a pharmacologically relevant concentration of doxorubicin does not cause direct mechanism-based inactivation of hepatic microsomal CYPs or NADPH-CYP reductase, suggesting that the ability of doxorubicin to depress hepatic CYP-mediated biotransformation in vivo is due to lipid peroxidation mediated heme destruction, altered heme metabolism, and (or) decreased expression of selected CYP enzymes.
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PMID:Lack of mechanism-based inactivation of rat hepatic microsomal cytochromes P450 by doxorubicin. 1054 22

The five selective serotonin reuptake inhibitors (SSRIs), fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram, have similar antidepressant efficacy and a similar side effect profile. They differ, however, in their pharmacokinetic properties. Under steady-state concentrations, their half-lives range between 1 and 4 days for fluoxetine (7 and 15 days for norfluoxetine) and between 21 (paroxetine) and 36 (citalopram) hr for the other SSRIs. Sertraline and citalopram show linear and fluoxetine, fluvoxamine, and paroxetine nonlinear pharmacokinetics. SSRIs underlie an extensive metabolism with high interindividual variability, whereby cytochrome P450 (CYP) isoenzymes play a major role. Therefore, resulting blood concentrations are highly variable between individuals. Except for N-demethylated fluoxetine, metabolites of SSRIs do not contribute to clinical actions. Therapeutically effective blood concentrations are unclear so far, although there is evidence for minimal effective and upper-threshold concentrations that should not be exceeded. Paroxetine and, to a lesser degree, fluoxetine and norfluoxetine are potent inhibitors of CYP2D6 and fluvoxamine of CYP1A2 and CYP2C19. This can give rise to drug-drug interactions that may have no effect, lead to intoxication, or improve the therapeutic response. These different pharmacokinetic properties of the five SSRIs, especially their drug-drug interaction potential, should be considered when selecting a distinct SSRI for treatment of depression or other disorders with a suggested dysfunction of the serotonergic system in the brain.
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PMID:Pharmacokinetics of selective serotonin reuptake inhibitors. 1067 11

Diseases are a major cause of variation in drug response. Although many different diseases are known that have an effect on the pharmacokinetics or sometimes the pharmacodynamics of a drug, disorders associated with a so-called acute phase response (APR) are the most important in this respect. During APR, for example caused by tissue damage or invasion of a pathogen, a group of symptoms can be observed that often include fever, lassitude, inhibition of gastric function and synthesis of acute phase proteins. All phases that together determine the pharmacokinetic profile of a drug, absorption, distribution, metabolism and excretion, can be affected during APR. From a clinical point of view however, the effects on absorption and metabolism are the most relevant. For drugs that are given orally, a slower absorption rate is often observed during APR due to a delayed gastric emptying. Even more important from a clinical point of view is the depression of biotransformation capacity in the liver during APR, especially affecting the enzymes of the cytochrome P450 (CYP450) complex. Although much has become known about the mechanism of this effect, a number of questions remain. Cytokines, nitric oxide and possibly the enzyme heme oxygenase are playing a role in a complex process that depends on a mutual interaction between Kupffer cells (macrophages) and hepatocytes in the liver. The clinician should be aware of unexpected changes in drug effects or residue levels due to cumulation of the compound during disease or after vaccination. In these situations, drugs that are excreted unchanged may be better alternatives.
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PMID:Cytochromes and cytokines: changes in drug disposition in animals during an acute phase response: a mini-review. 1068 82

St. John's wort (Hypericum perforatum) is an herbal remedy used widely for the treatment of depression. Recent clinical studies demonstrate that hypericum extracts increase the metabolism of various drugs, including combined oral contraceptives, cyclosporin, and indinavir. In this report, we show that hyperforin, a constituent of St. John's wort with antidepressant activity, is a potent ligand (K(i) = 27 nM) for the pregnane X receptor, an orphan nuclear receptor that regulates expression of the cytochrome P450 (CYP) 3A4 monooxygenase. Treatment of primary human hepatocytes with hypericum extracts or hyperforin results in a marked induction of CYP3A4 expression. Because CYP3A4 is involved in the oxidative metabolism of >50% of all drugs, our findings provide a molecular mechanism for the interaction of St. John's wort with drugs and suggest that hypericum extracts are likely to interact with many more drugs than previously had been realized.
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PMID:St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. 1085 61

Commercially available St. John's wort (Hypericum perforatum) extracts, preparations that are used in the treatment of depression, were examined for the potential to inhibit human cytochrome P450 (CYP) enzyme activities, specifically CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Crude extracts demonstrated inhibition of each of these five enzymes, with CYP2D6, CYP2C9, and CYP3A4 being more sensitive than CYP1A2 and CYP2C19. Extracts were fractionated by HPLC, and each of the fractions was tested for inhibition of these five CYPs to identify individual constituents with inhibitory activity. Several fractions were shown to possess inhibitory activity, including the fractions containing hyperforin (the putative active antidepressant constituent), I3,II8-biapigenin, and hypericin. Hyperforin and I3,II8-biapigenin were isolated from the extract, and inhibition constants for the five CYP activities were measured. In addition, three other constituents, hypericin, quercetin, and chlorogenic acid, were tested for inhibitory activity toward the CYP enzymes. The flavonoid compound I3,II8-biapigenin was shown to be a potent, competitive inhibitor of CYP3A4, CYP2C9, and CYP1A2 activities with K(i) values of 0.038, 0.32, and 0.95 microM, respectively. Hyperforin was a potent noncompetitive inhibitor of CYP2D6 activity (K(i) = 1.5 microM) and competitive inhibitor of CYP2C9 and CYP3A4 activities (K(i) = 1.8 and 0.48 microM, respectively). Hypericin also demonstrated potent inhibition of several CYP activities. These in vitro data indicate that St. John's wort preparations contain constituents that can potently inhibit the activities of major human drug-metabolizing enzymes and suggest that these preparations should be examined for potential pharmacokinetic drug interactions in vivo.
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PMID:Inhibition of human cytochrome P450 enzymes by constituents of St. John's Wort, an herbal preparation used in the treatment of depression. 1087 Dec 99

The effect of protein undernutrition on the activity of the smooth endoplasmic reticulum (microsomal) Ca2+-ATPase (SERCA) was investigated. After 12 weeks of ad libitum ingestion of low protein diet (5% protein), a significant depression (p <0.05) of liver ER Ca2+-ATPase activity (68.6% depression) was observed. However, no significant effects on cytochrome P450 activity and relative liver weight were found. It is proposed that low protein diet by inhibiting the rat liver SERCA activity, might increase the cytosolic free calcium ion concentration ([Ca2+]) and promote the development of liver tumor. The possible mechanisms of low protein diet induced inhibition of SERCA activity are highlighted.
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PMID:The Ca2+-transporting activity of rat liver microsomes in response to protein undernutrition: implications for liver tumor promotion. 1096 66

1. The effect of the fluorinated ether anaesthetics enflurane and isoflurane in mice on haem metabolism and regulation in different metabolic states, such as depression and induction of cytochrome P450 produced by allylisopropylacetamide (AIA) and imidazole, respectively, was investigated. 2. Mice previously treated with AIA (350 mg/kg, i.p.) or imidazole (400 mg/kg, i.p.) received a single dose (1 mL/kg, i.p.) of enflurane or isoflurane and were killed 20 min after anaesthetic administration. 3. Induction of delta-aminolevulinic acid synthetase (ALA-S) activity was found, as expected, in animals receiving AIA and also in animals treated with AIA plus anaesthesia, but no change in the activity of either porphobilinogenase (PBGase) or porphobilinogen deaminase (PBG-D) activities was detected in these two groups of animals. An additional increase in haem destruction was observed in the AIA plus isoflurane-treated group. When mice were injected with imidazol alone or in combination with the anaesthetics, ALA-S activity was increased 50-90% in all groups, but again no change in PBGase or PBG-D activity was observed. Haem oxygenase was diminished in mice receiving imidazole and anaesthesia. 4. In conclusion, neither enflurane nor isoflurane caused additional disturbances in haem metabolism to those produced by AIA or imidazole alone.
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PMID:Relevance of cytochrome P450 levels in the actions of enflurane and isoflurane in mice: studies on the haem pathway. 1102 72

I believe there are four essential elements in the management of patients with irritable bowel syndrome (IBS): to establish a good physician-patient relationship; to educate patients about their condition; to emphasize the excellent prognosis and benign nature of the illness; and to employ therapeutic interventions centering on dietary modifications, pharmacotherapy, and behavioral strategies tailored to the individual. Initially, I establish the diagnosis, exclude organic causes, educate patients about the disease, establish realistic expectations and consistent limits, and involve patients in disease management. I find it critical to determine why the patient is seeking assistance (eg, cancer phobia, disability, interpersonal distress, or exacerbation of symptoms). Most patients can be treated by their primary care physician. However, specialty consultations may be needed to reinforce management strategies, perform additional diagnostic tests, or institute specialized treatment. Psychological co-morbidities do not cause symptoms but do affect how patients respond to them and influence health care-seeking behavior. I find that these issues are best explored over a series of visits when the physician-patient relationship has been established. It can be helpful to have patients fill out a self-administered test to identify psychological co-morbidities. I often use these tests as a basis for extended inquiries into this area, resulting in the initiation of appropriate therapies. I encourage patients to keep a 2-week diary of food intake and gastrointestinal symptoms. In this way, patients become actively involved in management of their disease, and I may be able to obtain information from the diary that will be valuable in making treatment decisions. I do not believe that diagnostic studies for food intolerances are cost-effective or particularly helpful; however, exclusion diets may be beneficial. I introduce fiber supplements gradually and monitor them for tolerance and palatability. Synthetic fiber is often better-tolerated than natural fiber, but must be individualized. In my experience, excessive fiber supplementation often is counterproductive, as abdominal cramps and bloating may worsen. Antidiarrheal agents are very effective when used correctly, preferably in divided doses. I use them in patients in anticipation of diarrhea and especially in those who fear symptoms when engaged in activities outside the home. I encourage patients to make decisions as to when and how much to use. However, almost always, a morning dose before breakfast is used (loperamide, 2 to 6 mg) and, perhaps again later in the day when symptoms of diarrhea are prominent. I prefer antispasmodics to be used intermittently in response to periods of increased abdominal pain, cramps, and urgency. For patients with daily symptoms, especially after meals, agents such as dicyclomine before meals are useful. For patients with infrequent but severe episodes of unpredictable pain, sublingual hyoscyamine often produces rapid relief and instills confidence. In general, I recommend that oral antispasmodics be used for a limited period of time rather than indefinitely, and generally for periods of time when symptoms are prominent. For chronic visceral pain syndromes, I recommend small doses of tricyclic antidepressants. These agents are especially effective in diarrhea-predominant patients with disturbed sleep patterns but may be unacceptable to patients with constipation. I educate patients that side effects occur early and benefits may not be apparent for 3 to 4 weeks. I consider using SSRIs in low doses in patients with constipation-predominant IBS; cisapride, 10 to 20 mg three times per day, also may be beneficial. When taken with drugs that inhibit cytochrome P450, cisapride has been associated with serious cardiac arrhythmias caused by QT prolongation, including ventricular arrhythmias and torsades de pointes. These drugs include the azole fungicides; erythromycin, clarithromycin, and troleandomycin; some antidepressants; HIV protease inhibitors; and others. In patients with IBS with mild to moderate co-morbid depression, I have found that the use of SSRIs such as paroxetine, fluoxetine, or sertraline may be beneficial. It is important to tell patients that anxiety and disturbed sleep may occur during the first 10 days and benefits may not occur for 3 to 4 weeks. I prescribe a small amount of a short-acting benzodiazepine such as alprazolam, 0.5 mg two times per day, to control these symptoms. For generalized anxiety without depression, buspirone or clonazepam may be useful. I have found that patients who also have associated panic disorder may benefit from a benzodiazepine, tricyclic antidepressant, or an SSRI. However, these patients are best managed in conjunction with a psychiatrist or psychologist. I consider the use of alternative therapies in patients who fail to respond to conventional measures and who are receptive to alternative strategies. These include general relaxation techniques such as biofeedback and hypnosis therapies.
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PMID:Irritable Bowel Syndrome. 1109 67

Geriatric patients with major depression present clinical challenges not encountered in younger individuals, including a greater incidence of medical comorbidity, higher rates of multiple medication use, changes in drug metabolism due to age or physical illness, and increased sensitivity to antidepressant side effects. Nevertheless, successful treatment of depressive disorders in the elderly improves mental and physical functioning, decreases morbidity and perhaps mortality, and enhances quality of life. Recent research indicates that newer antidepressants are effective for late life depression and safer for older individuals. Among newer antidepressants, venlafaxine has a pharmacological profile that makes it an attractive choice for geriatric patients. It has limited potential to interact with other medications because it only weakly inhibits the cytochrome P450 system and binds to plasma proteins at a low level. Dosing may have to be adjusted for patients with renal failure, but typically not for those with liver disease or other medical conditions. Data from three double-blind and four open clinical trials support the safety and efficacy of venlafaxine for geriatric depression. Patients may experience transient, generally tolerable side effects such as insomnia, nausea, agitation, or dry mouth early in treatment, but more serious problems such as falls or cardiac rhythm disturbances seem to be rare. Treatment emergent hypertension occurs in a small percentage of older patients, generally at doses above 150 mg/day. Finally, emerging data suggest that venlafaxine may be effective for conditions such as stroke, anxiety, and neuropathic pain that frequently accompany depressive disorders in the elderly.
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PMID:Efficacy of venlafaxine in geriatric depression. 1109 16

Reboxetine is a novel selective norepinephrine inhibitor that has been evaluated in the treatment of patients with depression. Reboxetine is a racemic mixture, and the (S,S)-(+)-enantiomer appears to be the more potent inhibitor. However, the ratio of the areas under the concentration-time curves of the (S,S)-(+)- and (R,R)-(-)-enantiomers in vivo is approximately 0.5. There is no evidence for chiral inversion. Differences in the clearances of the 2 enantiomers may be explained by differences in protein binding. The pharmacokinetics of reboxetine are linear following both single and multiple oral doses up to a dosage of 12 mg/day. The plasma concentration-time profile following oral administration is best described by a 1-compartment model, and the mean half-life (approximately 12 hours) is consistent with the recommendation to administer the drug twice daily. Reboxetine is well absorbed after oral administration. The absolute bioavailability is 94.5%, and maximal concentrations are generally achieved within 2 to 4 hours. Food affects the rate, but not the extent, of absorption. The distribution of reboxetine appears to be limited to a fraction of the total body water due to its extensive (>97%) binding to plasma proteins. The primary route of reboxetine elimination appears to be through hepatic metabolism. Less than 10% of the dose is cleared renally. A number of metabolites formed through hepatic oxidation have been identified, but reboxetine is the major circulating species in plasma. In vitro studies show that reboxetine is predominantly metabolised by cytochrome P450 (CYP) 3A4; CYP2D6 is not involved. Reboxetine plasma concentrations are increased in elderly individuals and in those with hepatic or renal dysfunction, probably because of reduced metabolic clearance. In these populations, reboxetine should be used with caution, and a dosage reduction is indicated. Ketoconazole decreases the clearance of reboxetine, so that the dosage of reboxetine may need to be reduced when potent inhibitors of CYP3A4 are coadministered. Quinidine does not affect the in vivo clearance of reboxetine, confirming the lack of involvement of CYP2D6. There is no pharmacokinetic interaction between reboxetine and lorazepam or fluoxetine. Reboxetine at therapeutic concentrations has no effect on the in vitro activity of CYP1A2, 2C9, 2D6, 2E1 or 3A4. The lack of effect of reboxetine on CYP2D6 and CYP3A4 was confirmed by the lack of effect on the metabolism of dextromethorphan and alprazolam in healthy volunteers. Thus, reboxetine is not likely to affect the clearance of other drugs metabolised by CYP isozymes.
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PMID:Clinical pharmacokinetics of reboxetine, a selective norepinephrine reuptake inhibitor for the treatment of patients with depression. 1119 74


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