Cytochrome P450 isoenzyme inhibitors

Cimetidine is a non-specific cytochrome P450 isoenzyme inhibitor, but it would seem that in most cases, with the exception of loratadine, these enzyme inhibitory effects do not significantly affect the metabolism of antihistamines. More recent evidence has shown cimetidine can also affect drug transporter proteins, in particular it may inhibit organic cation transporters. However, it probably does not affect anion transporter proteins since it does not affect the plasma pharmacokinetics of fexofenadine, which is a substrate of these transporters. ... 

Metabolism is still a barrier to be overcome. Some QSAR, pharmacophore, protein, and rule-based models are available to predict substrates and inhibitors of a specific cytochrome P450 isoenzyme [47-55]. 

Imidazole antimycotics, ketoconazole, clotrimazole, and miconazole are potent inhibitors of various cytochrome P450-isoenzymes that also affect the metabolism of retinoids. They were fust shown to inhibit the metabolism of RA in F9 embryonal carcinoma cells. When tested in vitm liarazole, a potent CYP-inhibitor, suppressed neoplastic transformation and upregulated gap junctional communication in murine and human fibroblasts, which appeared to be due to the presence of retinoids in the serum component of the cell culture medium. Furthermore, liarazole magnified the cancer chemopreventive activity of RA and (3-carotene in these experiments by inhibiting RA-catabolism as demonstrated by absence of a decrease in RA-levels in the culture medium in the presence of liarazole over 48 h, whereas without liarazole 99% of RA was catabolized. In vivo, treatment with liarazole and ketoconazole reduced the accelerated catabolism of retinoids and increased the mean plasma all-irans-RA-concentration in patients with acute promyelocytic leukemia and other cancels. 

CYP. cytochrome P450 isoenzyme HIV, human immunodeficiency vims INR, International Normalized Ratio LFTs, liver function tests MAOI, monoamine oxidase inhibitor PT, prothrombin time TCA, tricyclic antidepressant. 

The answer is d. (Kai ung, p 505.) Fluoxetine is a highly selective serotonin re uptake inhibitor (55RI) acting on the 5-1 IT transporter. It forms an active metabolite that is effective for several days. Selective serotonin reuptake inhibitors are inhibitors of cytochrome P450 isoenzymes, which is the basis of potential drug-drug interactions... 

Aprepitant is a moderate CYP3A4 inhibitor. Aprepitant should not be used concurrently with pimozide or cisapride. Inhibition of cytochrome P450 isoenzyme 3A4 (CYP3A4) by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions. Aprepitant is contraindicated in patients who are hypersensitive to any component of the product. 

The taxanes are practically insoluble in water and solubility is limited to mixtures of ethanol with poly-ethoxylated castor oil. They are generally administered in 3-24 hour infusions. The taxanes are for 90-95% plasma protein bound and primarily metabolized by P450 enzymes in the liver. Less than 10% is excreted in the urine as parent compounds. The elimination half-life of docetaxel is approximately 10 hours while that of paclitaxel has been vary-ingly reported between 5 and 50 hours. Inhibitors of the cytochrome P450 isoenzyme Cyp3A4, like keto-conazole and erythromycine, are contraindicated. 

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]. 

Cimetidine is an inhibitor of several cytochrome P450 isoenzymes and so potentiates a large number of drugs ordinarily metabolised by that system, notably, theophylline, warfarin, phenytoin and propranolol. Depending on the interacting drug, up to 50% inhibition of metabolism may occur when cimetidine 2000 mg/d is taken. 

Cilostazol Inhibitors of cytochrome P450 isoenzyme CYP3A4 are predicted to increase the serum levels of cilostazol or its active metabolite (all SSRIs potentially affected). 

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...

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. ... 

Fluvoxamine decreased the mean total plasma clearance of ropivacaine by 68% from 354 to 112 mL/minute, and almost doubled the half-life of ropivacaine in a randomised, crossover study in 12 healthy subjects. Fluvoxamine was given at a dose of 25 mg twice daily for 2 days, and a single 40 mg intravenous dose of ropivacaine was given over 20 minutes one hour after the morning dose of fluvoxamine on the second day. Fluvoxamine is a potent inhibitor of the cytochrome P450 isoenzyme CYP1A2 and so reduces the metabolism of ropivacaine to its major metabolite 3-hydroxyropivacaine. In one study in healthy subjects the combination of fluvoxamine with erythromycin, an inhibitor of CYP3A4, which on its own has little effect on the pharmacokinetics of ropivacaine, was found to decrease the clearance of ropivacaine more than fluvoxamine alone. ... 

Parecoxib is a parenteral drug that is rapidly metabolised in the liver to the active COX-2 inhibitor valdecoxib. Valdecoxib is predominantly metabolised by the cytochrome P450 isoenzymes CYP3A4 and CYP2C9. The interactions therefore are usually considered to he due to the effects of valdecoxib. 

An in vitro study found that the cytochrome P450 isoenzyme subfamily CYP3A, and to a lesser extent the isoenzyme CYP2C9, catalyse hydromorphone A-demethylation to norhydromorphone. Troleandomycin (an inhibitor of CYP3A) reduced norhydromorphone formation by about 45%. The clinical relevance of this is unknown. 

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. 

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