CYP3A4 effectiveness

Gomes LG, Huang N, Agrawal V, Mendonca BB, Bachega TA, Miller WL (2009) Extraadrenal 21-hydroxylation by CYP2C19 and CYP3A4 effect on 21-hydroxylase deficiency. J Clin Endocrinol Metab 94 89-95... 

The co-administration of drugs which induce the metabolic enzymes in the liver or small intestine can reduce the plasma concentrations of drugs which are substrates of the enzyme, leading to reduced drug effects. For example, the plasma concentrations of many drugs which are substrates of the enzyme CYP3A4, such as cyclosporine, are decreased by coadministration of rifampicin, which is an inducer of CYP3A4. 

EDWARDS D J, FITZSIMMONS M E, SCHUETZ E G, YASUDA K, DUCHARME M P, WARBASSE L H, WOSTER p M, SCHUETZ J D, WATKINS p (1999) 6, 7 -Dihydroxybergamottm in grapefruit juice and Seville orange juice effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. Clin Pharmacol Ther. 65 237-44. 

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. 

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... 

CYP3A4 and 2D6 are the major enzymes involved in the metabolism of galantamine. Pharmacokinetic studies with inhibitors of this system have resulted in increased galantamine concentrations or reductions in clearance. Similarly to donepezil, if inhibitors are given concurrently with galantamine, monitoring for increased cholinergic side effects should be done. Studies with inducers of these enzymes have not been completed.37... 

Theoretically buprenorphine metabolism could be inhibited by itraconazole, ketoconazole, grapefruit juice, and erythromycin or any other CYP3A4 inhibitor the effects may be greater than expected for the dose of buprenorphine being given may need to decrease buprenorphine dose. 

Conversely buprenorphine metabolism could by increased by carbamazepine, phenytoin, St. John s wort, efavirenz, and nevirapine, or any other CYP3A4 inducer the effects may be less than expected may need to increase buprenorphine dose. 

Buspirone generally is well tolerated and does not cause sedation. Most common side effects include dizziness, nausea, and headaches. Drugs that inhibit CYP3A4 (e.g., verapamil, diltiazem, itraconazole, fluvoxamine, nefa-zodone, and erythromycin) can increase buspirone levels. Likewise, enzyme inducers such as rifampin can reduce buspirone levels significantly. Bupirone may increase blood pressure when coadministered with an monoamine oxidase inhibitor (MAOI). 

Ball, S.E. et al. (1999). Population distribution and effects on drug metabolism of a genetic variant in the 5 promoter region of CYP3A4. Clin. Pharmacol. Ther., 66, 288-94. 

Wandel, C. etal. (2000). CYP3A activity in African American andEuropean American men population differences and functional effect of the CYP3A4 lB5 -promoter region polymorphism. Clin. Pharmacol. Ther., 68, 82-91. 

St. John s wort, which has become very popular for the treatment of depression, has been shown to induce intestinal P-gp and intestinal and hepatic CYP3A4 in humans [140]. That mechanism explains the significant reduction in cyclosporin and anti-aids (e.g., indinavir) plasma concentrations. It is likely that similar effects will be noted with the compounds listed in Table 8 (although the effects noted in Table 8 are in the opposite direction of those seen in the presence of St. John s wort). 

As the divalent cation effect on CYP3A4 activity appears to be substrate dependent, the benefit of including MgCl2 (1-30 mM) in the oxidative incubation should be examined for each substrate. 

Ito, K., Kusuhara, H., Sugiyama, Y., Effects of intestinal CYP3A4 and P-glycoprotein on oral drug absorption -theoretical approach, Pharm. Res. 

Many authors have suggested that gut wall CYP3A4 and P-gp act in a concerted manner to control the absorption of their substrates [1, 17, 32, 44-47]. This is based on the large overlap of substrates between the two [48], and the proximity of their expression within the gut wall. Thus, it is proposed [44] that P-gp effectively recycles its substrates, thereby allowing CYP3A4 several opportunities to metabolize compounds in the gut. In this way, a small amount of CYP3A4 in the gut wall (relative to the liver content) can exert a profound extraction of the compound. 

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