CYP interactions

Ketoconazole (a potent inhibitor of CYP3A4) has been shown to increase the oral bioavailability of cyclosporin from 22 to 56% [50]. This consisted of a 1.8-fold decrease in systemic clearance combined with a 4.9-fold decrease in oral clearance. The authors estimated that hepatic extraction was decreased only 1.15-fold, whereas the oral bioavailability increased 2.6-fold and the observation was attributed to decreased intestinal metabolism. Erythromycin was also shown to increase the oral bioavailability of cyclosporin A 1.7-fold, while pre-treatment with rifampin (an inducer of CYP3A4) decreased oral bioavailability of cyclosporin from 27% to 10% due to a 4.2-fold increase in oral clearance but only a 1.2-fold increase in systemic clearance. Floren et al. [51] have also shown that ketoconazole can double the oral bioavailability of tacrolimus in man by inhibiting gut wall CYP3A4. 

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Fluoxetine and paroxetine are potent inhibitors of the CYP2D6 isoenzyme, and this contributes to potential drug interactions (see drug interactions). In contrast, fluvoxamine is an inhibitor of CYP3A4, whereas citalopram, escitalopram, and sertraline have more modest CYP interactions. 

Aprepitant NKj-receptor blocker in CNS Interferes with vomiting reflex no effect on 5-HT, dopamine, or steroid receptors Effective in reducing both early and delayed emesis in cancer chemotherapy Given orally IV fosaprepitant available fatigue, dizziness, diarrhea CYP interactions... 

In metabolism and distribution studies, armodafinil s primary metabolic pathway is via a non-CYP-related amide hydrolysis. As a result, concomitant medications having CYP-interactions are not likely to have deleterious effects (or drug-drug interactions) on the pharmacokinetic profile of armodafinil. The details of the pharmacokinetics of armodafinil are listed in Table 1. 

The problems of deducing dmg-CYP interactions are compounded by the fact that very few crystal structures have been resolved to date, in part due to the difficulties of crystallizing membrane proteins. There are few reference three-dimensional structures from which to work when con-... 

Substrate InU-ractions with Cytochromes P450 Substrates for CYPs interact with the heme-thiolate, displacing the oxygen from the sixth coordination site. An example of this is shown in Eigure 8.12, which portrays the... 

Many of the more recent publications on in-silico assessments of CYP interactions employ non-linear approaches. They are well suited to be applied in cases were the model interpretability is less of an issue. In fhe same venue, classification models have been developed. Although coarse-grained, these models can be used as one of a number of filters fo pick fhe mosf inferesfing compounds for subsequent experimental profiling. These classification models may also be a way to overcome the problem of noisy dafa, which are nof reliable enough for fhe generation of a quantitative model [68-83,136]. 

Other assays for assessing CYP clearance are also employed, although often less widely or with lower compound throughput. Recombinant CYP enzymes allow the determination of the kinetic parameters for metabolism of individual compounds by individual CYPs. Recombinant CYPs also provide an avenue to assessing and understanding the potential for drug-drug interactions that may occur between two or more compounds. 

Use of zileuton is uncommon due to the need for dosing four times a day, potential drug interactions, and the potential for hepatotoxicity with the resulting need for frequent monitoring of liver enzymes. In patients started on zileuton, serum alanine aminotransferase concentrations should be monitored before treatment begins, monthly for the first 3 months, every 2 to 3 months for the remainder of the first year, and then periodically thereafter for as long as the patient continues to receive the medication. Zileuton also inhibits the cytochrome P-450 (CYP) mixed function enzyme system and has been shown to decrease the clearance of theophylline, R-warfarin and propranolol.34... 

Only a small number of drug interactions have been reported with donepezil. In vitro studies show a low rate of binding of donepezil to cytochrome P-450 (CYP)3A4 or 2D6. Whether or not donepezil has the potential for enzyme induction is not known. No interactions with theophylline, cimeti-dine, warfarin, digoxin, or ketoconazole have been documented. In vitro studies show that inhibitors of CYP3A4 and 2D6 have the potential to inhibit the metabolism of donepezil. The clinical relevance of this is unknown. However, monitoring for possible increased peripheral side effects is advised... 

Most pharmacokinetic interactions in transplantation occur due to interactions with the CYP enzyme system however, several interactions have been shown to occur via alternative mechanisms. One of the most notable is that seen between tacrolimus and some of the prokinetic agents. Cisapride and metoclopramide have been shown to increase the absorption of tacrolimus by enhancing gastric emptying.41... 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

Rifampin Hepatic abnormalities monitor LFTs Reddish-orange discoloration of secretions (e.g., urine, sweat, tears) Potent inducer of CYP-mediated metabolism evaluate for drug-drug interactions... 

The majority of antiretroviral medications are metabolized by the cytochrome P-450 enzyme system (CYP). Therefore, it is important to review patient medication profiles for drugs that may interact with antiretroviral drugs. 

Ethnic differences have been shown to influence response to psychotropic medications. Much of the focus on the explanation for such differences has been on drug-metabolizing (CYP) enzymes of the liver and their sway over pharmacokinetic factors. It is now well recognized that differences in the distribution of polymorphic variants of CYP enzymes exist between different ethnic groups. However, within ethnic groups there are considerable inter-individual variations in drug kinetics, which may not be accounted for solely by genetic variation. Responses to pharmacotherapy are multifaceted and involve the interaction of environmental and... 

Murray, M. (2006). Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents. /. Pharm. Pharmacol, 58, 871— 85. 

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