Cytochrome P450 isoenzyme inducers

By using in vitro preparations of human enzymes it is possible to predict those antibiotics that will adversely affect the metabolism of other drugs [110]. Such studies have shown that rifaximin, at concentrations ranging from 2 to 200 ng/ml, did not inhibit human hepatic cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 [34], In an in vitro hepatocyte induction model, rifaximin was shown to induce cytochrome P450 3A4 (CYP3A4) [34], an isoenzyme which rifampicin is known to induce [109],... 

Memantine is not a major substrate for hepatic cytochrome P450 isoenzymes and has not been shown to significantly inhibit or induce these enzymes. However, memantine is partially excreted by renal tubular secretion. Thus, concomitant use of other medications that use the same renal system (i.e., triampterene, hydrochlorothiazide, digoxin, cimetidine, ranitidine, metformin, and quinidine) may affect plasma levels of both drugs (Namenda 2005). Memantine should not be used in combination with other NMDA receptor antagonists, such as amantadine or dextromethorphan, because these combinations have not been formally studied. The clearance of memantine can be reduced when the urine is alkalinized, such as with the concomitant use of sodium bicarbonate or carbonic anhy-... 

Oral lacosamide is rapidly and completely absorbed in adults, with no food effect. Bioavailability is nearly 100%. The plasma concentrations are proportional up to 800 mg orally. Peak concentrations occur from 1 to 4 hours after oral dosing, with an elimination half-life of 13 hours. There are no active metabolites and protein binding is minimal. Lacosamide does not induce or inhibit cytochrome P450 isoenzymes, so drug interactions are negligible. 

Zaleplon is primarily metabolized by aldehyde oxidase and use with inhibitors of this enzyme, such as cimetidine, may result in increased plasma concentrations of zaleplon. Zaleplon is also partly metabolized by the cytochrome P450 isoenzyme CYP3A4 and, consequently, caution is advised when zaleplon is given with drugs that are substrates for, or potent inhibitors of, this isoenzyme. Cimetidine is also an inhibitor of CYP3A4 and thus inhibits both the primary and secondary metabolic pathways of zaleplon. Use with rifampicin or other potent enzyme-inducing drugs may accelerate the metabolism of zaleplon and reduce its plasma concentrations [40]. 

Paclitaxel is metabolized by the cytochrome P450 isoenzymes CYP2C and CYP3A4 (53), and drugs that inhibit or induce these isozymes would be expected to alter the metabolism of paclitaxel. In vitro ranitidine, diphenhydramine, vincristine, vinblastine, and doxorubicin had little or no effect on the metabolism of paclitaxel, but... 

The question rose whether the CPH-induced 44,000 molecular weight polypeptide is a cytochrome P450-isoenzyme. Thus, induction experiments were carried out in which sahne-treated rats were compared with phenobarbital- and CPH-treated rats. Analysis of the polypeptide composition of the microsomal fraction from the phenobarbital group indicated a significant... 

In vitro studies KOI Cynthia Wenner/ Bastyr University Investigate the correlation between formulation composition and bioactivity of echinacea Study herb/drug interactions by examining echinacea s effects on drug-induced inhibition of Cytochrome P450 isoenzymes involved in drug metabolism... 

I Drug-Drug Interactions. Carbamazepine induces the hepatic cytochrome P450 isoenzymes (1A2, 3A4, 2C9/10, and 2D6), which increases the metabolism of many medications, such as anticonvulsants (i.e., lamotrigine, topiramate, and valproate), antidepressants (i.e., tricyclics and bupropion), antipsychotics (i.e., clozapine, haloperi-dol, fluphenazine, olanzapine, and thiothixene), benzodiazepines, oral contraceptives, and protease inhibitors. " Women who receive carbamazepine require higher dosages of oral contraceptives or alternative contraceptive methods." ... 

Table 30.4 Nonexhaustive list of substrates for, and inducers and inhibitors of some human liver cytochrome P450 isoenzymes...

Cruciferous vegetables, such as brussels sprouts, cabbage, and broccoli, contain substances that are inducers of the cytochrome P450 isoenzyme CYP1A2. Chemicals formed by burning meats additionally have these... 

Ten healthy subjects were given losartan 50 mg daily for a week and then, after a 6-day washout period, losartan 50 mg daily with rifampicin 300 mg twice daily for a week. It was found that rifampicin reduced the AUC of losartan by 36%, reduced its half-life from 2 to 0.9 hours, and increased its clearance by 60%. The AUC of the active metabolite, E3174, was reduced by 41% and its half-life was reduced from 5.1 to 2.5 hours. Diastolic blood pressure was significantly reduced by losartan alone, but not by the combination. The presumed reason for this interaction is that rifampicin (a recognised enzyme inducer) increases the metabolism of losartan to its active metabolite by the cytochrome P450 isoenzyme CYP2C9. 

Part of the explanation for the increased C3S1S depression is that both alcohol and some of the tricyclics, particularly amitriptyline, cause drowsiness and other CNS depressant effeets, which can be additive with the effects of alcohol. The sedative effects have been reported to be greatest with amitriptyline, then doxepin and imipramine, followed by nortriptyline, and least with amoxapine, clomipramine, desipramine, and protriptyline. In addition acute alcohol intake causes marked increases (100 to 200%) in the plasma levels of amitriptyline, probably by inhibiting its first pass metabolism. Alcohol-induced liver damage could also result in impaired amitriptyline metabolism. The lower serum levels of imipramine and desipramine seen in abstinent alcoholics are attributable to induction of the cytochrome P450 isoenzymes by alcohol. ... 

The interaction between alcohol and vitamin A is complex. They have overlapping metabolic pathways a similar 2-step process is involved in the metabolism of both alcohol and vitamin A, with alcohol dehydrogenases and acetaldehyde dehydrogenases being implicated in the conversion of vitamin A to retinoic acid. Alcohol appears to act as a competitive inhibitor of vitamin A oxidation. In addition, chronic alcohol intake can induce cytochrome P450 isoenzymes that appear to increase the breakdown of vitamin A (retinol and retinoic acid) into more polar metabolites in the liver, which can cause hepatocyte death. So chronic alcohol consumption may enhance the intrinsic hepatotoxicity of high-dose vitamin A. Alcohol has also been shown to alter retinoid homoeostasis by increasing vitamin A mobilisation from the liver to extrahepatic tissues, which could result in depletion of hepatic stores of vitamin A. ... 

Morphine is metabolised by glucuronidation by UDP-glucuronyltrans-ferases, mainly to one active and one inactive metabolite. The glucuronidation of morphine can be induced or inhibited by various drugs. Morphine is not significantly affected by the cytochrome P450 isoenzymes. The semi-synthetic morphine analogues, hydromorphone and ox-ymorphone, are metabolised similarly. 

The manufacturers have done several interaction studies to find out whether parecoxib or valdecoxib can inhibit or induce the cytochrome P450 isoenzymes CYP2C9, CYP2D6, CYP2C19, and CYP3A4 and thereby determine their potential to interact with drugs metabolised by these isoenzymes. 

Although interaction studies have not been performed, the metabolism of buprenorphine is mediated by the cytochrome P450 isoenzyme CYP3A4 and therefore drugs that induce this enzyme such as carbamazepine, phe-... 

Efavirenz and nevirapine induce the metabolism of methadone (possibly by the cytochrome P450 isoenzyme CYP3A4, or CYP2B6 ), which results in reduced levels and effects. In contrast, delavirdine is an inhibitor... 

Buprenorphine is a substrate for the cytochrome P450 isoenzyme CYP3A4 and inducers of CYP3A enzymes such as efavirenz would be expected to increase buprenorphine clearance, whereas delavirdine, which is an inhibitor of CYP3A, would be expected to reduce the CYP3A-mediated metabolism of buprenorphine to norbuprenorphine. 

Not known. The findings are the opposite of those originally predicted based on in vitro data showing inhibition of methadone metabolism (principally mediated by the cytochrome P450 isoenzyme CYP3A). One study found a slight increase in methadone elimination, but this was not mediated by C YP3A. It is possible that these protease inhibitors induce the... 

Fentanyl is metabolis by the cytochrome P450 isoenzyme CYP3A4 and rifampicin, a potent inducer of CYP3A4, appears to reduce its serum levels and pharmacological efficacy. Thus an increase in fentanyl dosage may be ne ed in patients taking rifampicin. ... 

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