Induction of CYP-mediated metabolism

Induction of CYP-mediated metabolism requires prior exposure of the hepatocyte s CYP-synthesis mechanism to a chemical inducer. The inducer signals the synthetic mechanisms to upregulate the production of one or more CYP isoforms, a process that takes time. Consequently, evidence of increased CYP activity is of slow onset following initiation of exposure to the inducer, and conversely slowly reverts to baseline after the inducer is removed (46,47). Enhancement of CYP expression/activity due to chemical induction therefore reflects prior, but not necessarily current, exposure to the inducer. Nuclear receptors, such as the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), have been identified as key elements in the process of transcriptional activation (48-56). 

ST JOHN S WORT SULPHONYLUREAS i hypoglycaemic efficacy 1 plasma levels of sulphonylureas by induction of CYP-mediated metabolism Watch for and warn patients about symptoms of hyperglycaemia - For signs and symptoms of hyperglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hyperglycaemia... 

ST JOHN S WORT IRINOTECAN L plasma concentrations of irinotecan and risk of l therapeutic efficacy. The effects may last for 3 weeks after discontinuation of CYP-inducer therapy Due to induction of CYP3A4-mediated metabolism of irinotecan Avoid concomitant use when ever possible if not, t dose of irinotecan by 50%... 

TERBINAFINE PROGESTOGENS i progestogen levels, which may lead to a failure of contraception or poor response to treatment of menorrhagia Induction of the CYP-mediated metabolism of oestrogens Patients should be advised to use an alternative method of contraception during terbinafine therapy and for 1 month after its discontinuation... 

Figure 5.36 Mechanism of the receptor-mediated induction of CYP4A by a chemical such as the drug clofibrate. The inducer-receptor (PPAR) complex enters the nucleus, binds with RXR, and the complex binds to the receptor response elements in the CYP gene. This induces the production of CYP4A mRNA, which leads to the production of CYP4A protein and functional enzyme. Alternatively, the drug may perturb lipid metabolism leading to increases in a lipid(s), which will bind to the receptor and cause the same response. Abbreviations PPAR, peroxisome proliterator-activated receptor RXR, retinoid X receptor.

By one year post liver transplant both CYP expression and activity are similar to those of normal subjects [67]. Some interesting effects are observed in the first six months after transplant, but some may be due to the induction of specific enzymes by therapeutic agents used in this period. The observation of a tenfold increase in hepatic CYP3A4 content at ten days which then returns to normal at six months is probably due to the administration of prednisolone in the early postoperative period [69]. Other observations are more difficult to explain. An eightfold increase in CYP2E1 as measured by the chlorzoxazone metabolic ratio has been detected in the first month post transplant [70]. CYP2E1-mediated NAPQI formation from paracetamol is also increased by around 137% and 81% on days two and ten post transplant, and returns to normal after six months [71]. 

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