Cytochrome P-450 isoenzymes

FIGURE 7-8. Pharmacologic activity and metabolism of warfarin. CYP, cytochrome P-450 isoenzyme. (Reproduced from Haines ST, Zeolla M, Witt DM. Venous thromboembolism. In DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy A Pathophysiologic Approach. 6th ed. 

Tobacco smoke contains chemicals that induce the cytochrome P-450 isoenzymes 1A1,1A2, and 2E1. Theophylline is metabolized by 1A2 and 2E1, and therefore smoking leads to increased clearance and subsequently decreased plasma levels of the drug.15 Because most patients with COPD are current or past smokers, it is important to assess current tobacco use and adjust the theophylline dose as required based on altered plasma theophylline levels if tobacco use changes. 

CYP450, cytochrome P-450 isoenzyme. Data from references 36, 37, 38. 

Codeine, hydrocodone, morphine, methadone, and oxycodone are substrates of the cytochrome P-450 isoenzyme CYP2D6.47 Inhibition of CYP2D6 results in decreased analgesia of codeine and hydrocodone due to decreased conversion to the active metabolites (e.g., morphine and hydromorphone, respectively) and increased effects of morphine, methadone, and oxycodone. Methadone is also a substrate of CYP3A4, and its metabolism is increased by phenytoin and decreased by cimetidine. CNS depressants may potentiate the sedative effects of opiates. 

Several antidepressants, including most of the SSRIs, nefa-zodone, and duloxetine, are known to inhibit various cytochrome P-450 isoenzymes, thereby elevating plasma levels of substrates for those isoenzymes and thus potentially leading to increased adverse effects or toxicity of those drugs. The propensity to cause these drug interactions will vary with the particular antidepressant and the precise isoenzyme9,19,30 (Table 35-6). 

Vardenafil can cause QT-interval prolongation this effect in combination with certain anti-arrhythmic agents can lead to life-threatening arrhythmias. CYP, cytochrome P-450 isoenzyme. 

BUN, blood urea nitrogen CBC, complete blood cell count CNS, central nervous system CYP, cytochrome P-450 isoenzyme LFT, liver function test MAO, monoamine oxidase QTc, Q-T interval corrected for heart rate SCr, serum creatinine TMP-SMX, trimethoprim-sulfamethoxazole. 

Oral azoles are associated with significant interactions, particularly due to cytochrome P-450 isoenzymes. Medications that interact with azoles include warfarin, phenytoin, theophylline, rifampin, cyclosporine, and zidovudine. For patients receiving only a few doses, these interactions do not pose a significant risk. These interactions may pose a risk for patients receiving long-term suppressive therapy for recurrent infections. 

P. H., Cytochrome P 450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues, J. Pharmacol. Exp. Ther. 1990, 253, 387-394. 

A potentially powerful probe for sorting out the contribution of hydroperoxide-dependent and mixed-function oxidase-dependent polycyclic hydrocarbon oxidation is stereochemistry. Figure 9 summarizes the stereochemical differences in epoxidation of ( )-BP-7,8-dihydrodiol by hydroperoxide-dependent and mixed-function oxidase-dependent pathways (31,55,56). The (-)-enantiomer of BP-7,8-dihydrodiol is converted primarily to the (+)-anti-diol epoxide by both pathways whereas the (+)-enantiomer of BP-7,8-dihydrodiol is converted primarily to the (-)-anti-diol epoxide by hydroperoxide-dependent oxidation and to the (+)-syn-diol epoxide by mixed-function oxidases. The stereochemical course of oxidation by cytochrome P-450 isoenzymes was first elucidated for the methycholanthrene-inducible form but we have detected the same stereochemical profile using rat liver microsomes from control, phenobarbital-, or methyl-cholanthrene-induced animals (32). The only difference between the microsomal preparations is the rate of oxidation. 

The ability of different drugs to differentially inhibit and/or induce individual cytochrome P-450 isoenzymes has become critical in assessing the potential safety of drug molecules. Table 18.7 presents an overview of some of what we have come... 

TABLE 18.7. Examples of Xenobiotics Activated by Human Cytochrome P-450 Isoenzymes... 

Cytochrome P-450 Isoenzymes and Common Dru9S They Metabolize, Inhibit, and Induce ... 

The nucleoside agents do not have clinically significant drug interactions with the standard antituberculosis medications. However, the Pis and NNR-TIs may inhibit or induce cytochrome P-450 isoenzymes (CYP450) and thus, these drugs may alter the serum concentration of the rifamycins (Table 17(a) and (b)). 

Metabolism route Cytochrome P-450 isoenzymes Target enzymes AChE and BuChE Cytochrome P-450 isoenzymes... 

The biotransformation of the phenylpiperidines is primarily by hepatic phase I metabolism, catalysed by cytochrome P-450 isoenzymes. The elimination of alfentanil is significantly slowed in patients treated with erythromycin, a P-450 inhibitor, with delayed recovery and prolonged postoperative respiratory depression (Bartkowski and McDonnell 1990). Apart from pethidine and phenoperidine, none of the phenylpiperidines has pharmacologically active metabolites. 

In addition to the cytochrome P-450 isoenzymes, other enzymes carrying out phase I processes also show considerable polymorphism and thus variation in activity. 

Toftgard, R., Halpert, J. Gustafsson, J.-A. (1983) Xylene induces a cytochrome P-450 isoenzyme in rat liver similar to the major isozyme induced by phenobarbital. Mol. Pharmacol., 23,265-271... 

Due to first-pass metabolism, if administered alone lopinavir has varied plasma levels. This problem is overcome by adding ritonavir to the formulation. Its oral absorption is rapid, and its bioavailability is increased by food rich in fat content. Lopinavir is metabolized by cytochrome P-450 isoenzyme CYP3A4. Most of the drug in the plasma is bound to ai-acid glycoprotein. In combination with other antiretroviral agents, lopinavir is indicated for the treatment of HIV infection. 

The oral absorption of tipranavir is limited, and the bioavailability is increased with a high-fat meal. Its binding to plasma proteins is more than 99.9% where it binds to both ai -glycoprotein and albumin. Tipranavir is metabolized by cytochrome P-450 isoenzyme CYP3A4. Ritonavir decreases its first-pass clearance, and most of the drug is excreted in feces. In combination with other antiretroviral agents, tipranavir coadministered with ritonavir is indicated for HIV infection in patients who have received prior HIV treatment or have highly resistant HIV strains. 

The adverse effects of atazanavir include fever, jaundice/scleral icterus, myalgia and diarrhea. Its coadministration is not recommended with the drugs that induce cytochrome P-450 isoenzyme CYP3A4. Ritonavir increases plasma concentrations of atazanavir. It is an inhibitor of isoenzymes CYP3A4, CYP2C8 and UGT1A1. The coadministration of atazanavir with calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and phosphodiesterase 5 inhibitors should be carefully monitored. 

Assessment of the potential impact of hepatic dysfunction on the pharmacokinetic and adverse event profiles of donepezil is of primary importance, as donepezil is orally administered and subject to extensive first-pass metabolism. In addition, both preclinical and clinical studies have demonstrated that donepezil is metabolized primarily in the liver [8-11]. In vitro studies using human hepatic microsomes have shown that the cytochrome P-450 isoenzyme (CYP-3A4) is mostly responsible for the metabolism of donepezil, with CYP-2D6 playing a minor role. With this in mind, this study was designed to assess the effects of compromised hepatic function on the pharmacokinetics of donepezil HC1 [8-11]. 

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