Cytochrome P450 enzymes inhibitors

New applications of dioxolanes include the use of 37 as an anti-tussive , use of the dioxolane-containing furocoumarin dimer paradisin C 38, a natural product isolated from grapefruit, as a cytochrome P450 enzyme inhibitor <02T6631> and use of dioxolane 39 to activate wheat seeds towards germination and protect plants from water... 

With warfarin, one is always concerned about pharmacodynamic and pharmacokinetic drug interactions. None of the antiarrhythmic drugs mentioned above are likely to cause a pharmacodynamic interaction with warfarin. However, amiodarone is a cytochrome P450 enzyme inhibitor and increases warfarin s antithrombotic effects. Patients taking both drugs usually need to decrease their dose of warfarin. 

Rendic, S. DiCarlo, F. J. (1997). Human cytochrome P450 enzymes a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab. Rev., 29, 413-580. 

Ritonavir is a potent inhibitor of cytochrome P450 enzyme 3A and is used to reduce clearance of other Pis. 

Smital T, Luckenbach T, Sauerborn R, Hamdoun AM, Vega RL, Epel D (2004) Emerging contaminants - pesticides, PPCPs, microbial degradation products and natural substances as inhibitors of multixenobiotic defense in aquatic organisms. Mutat Res 552 101-117 Snyder MJ (2000) Cytochrome P450 enzymes in aquatic invertebrates recent advances and future directions. Aquat Toxicol 48 529-547... 

Fontana, E., Dansette, P.M. and Poli, S.M. (2005) Cytochrome P450 enzymes mechanism based inhibitors common sub-structures and reactivity. Current Drug Metabolism, 6, 413 -54. 

Taavitsainen P, Juvonen R, Pelkonen O (2001) In vitro inhibition of cytochrome P450 enzymes in human liver microsomes by a potent CYP2A6 inhibitor, trans-2-phenylcyclopropylamine (tranylcypromine), and its nonamine analog, cyclopropylbenzene. Drug Metab Dispos 29(3) 217-222... 

Relling, M.V., Evans, W.E., Fonne-Pfister, R., et al. (1989) Anticancer drugs as inhibitors of two polymorphic cytochrome P450 enzymes, debrisoquin and mephenytoin hydroxylase, in human liver microsomes. Cancer Res. 49, 68-71. 

Not an inducer or inhibitor of cytochrome P450 enzyme low drug interaction liability... 

Amprenavir is metabolized by the cytochrome P450 enzyme system and inhibits CYP3A4. Use caution when coadministering medications that are substrates, inhibitors, or inducers of CYP3A4, or potentially toxic medications that are metabolized by CYP3A4. 

Some selective serotonin re-uptake inhibitors are powerful inhibitors of cytochrome P450 enzymes and the metabolism of e.g. tricyclic antidepressants can be inhibited resulting in serious toxicity. Additive sedation can be expected when given in combination with CNS depressants such as benzodiazepines but also with alcohol. Selective serotonin re-uptake inhibitors should not be used in combination with monoamine oxidase inhibitors as fatal reactions have been reported. 

Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia after ima-tinib treatment and for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 and 6 hours (Tmax) following oral administration. Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. CYP3A4 was the primary enzyme responsible for the formation of the active metabolite. The overall mean terminal half-life of dasatinib is 3-5 hours. Adverse events included mild to moderate diarrhea, peripheral edema, and headache. Neutropenia and myelosuppression were common toxic effects. 

Mirtazapine does not significantly inhibit hepatic cytochrome P450 enzymes. Additive effects may occur when mirtazapine is combined with other drugs with sedative or vascular effects. Mirtazapine should not be used in combination with an MAOI or within 14 days of discontinuing treatment with an MAOI. When it is combined with fluvoxamine, a potent inhibitor of P450 enzymes— including 1A2, 2D6, and 3A4, which metabolizes mirtazapine—the plasma concentration of mirtazapine may be increased by up to fourfold (AnttUa et al. 2001 Demers et al. 2001). 

Aripiprazole is hepatically metabolized, mainly by two cytochrome P450 enzymes CYP 2D6 and CYP 3A4. Therefore, dosage adjustments are necessary when this medication is given with other medications that either inhibit or induce these enzymes. For example, the dose of aripiprazole should be halved when this medication is given with ketoconazole, a CYP 3A4 inhibitor, or at least decreased when given with fluoxetine, a CYP 2D6 inhibitor. When aripiprazole is given with CYP 3A4 inducers such as carbamazepine, the dose should be doubled. 

Galantamine is metabolized primarily by CYP 2D6 and 3A4, and levels may be altered by inducers or inhibitors of these enzymes. Galantamine has not been shown to inhibit major cytochrome P450 enzymes. However, the pharmacodynamic interactions associated with other cholinesterase inhibitors may occur. 

Harvey AT, Preskorn SH. Cytochrome P450 enzymes interpretation of their interactions with selective serotonin reuptake inhibitors (Part II). J Clin Psychopharmacol 1996 16 345-355. 

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