Enzyme inducing agents

When metabolic activation is used, S9 mix should not exceed 1-10 percent of the culture medium by volume. It has been shown that the S9 mix is clastogenic in CHO cells and mouse lymphoma cells (Cifone et al., 1987 Kirkland et al., 1989) but not in human lymphocytes, where blood components can inactivate active oxygen species which could cause chromosome damage. When S9 mix from animals treated with other enzyme-inducing agents such as phenobarbitone/beta-naphtho-flavone, is used, clastogenesis may be minimized (Kirkland et al., 1989). 

Tricyclic antidepressants are notorious for their risk to be involved in drug-drug interactions. Additive anticholinergic effects can be expected in combination with antihistamines, antipsychotics and anticholinergic-type anti-Parkinson agents. Hepatic enzyme-inducing agents increase their hepatic metabolism while enzyme inhibitors may potentiate the effects of tricyclics. Concomitant use with monoamine oxidase inhibitors will produce hypertension, hyperpyrexia and convulsions. 

Most glucocorticosteroid are metabolized in the liver to hydroxy- and ketosteroid metabolites which are excreted by the kidneys as glucuronides, sulfates and unconjugated products. Enzyme-inducing agents will diminish the efficacy of glucocorticosteroids. 

Cottrell, S., Oliver, K., Lake, B.G. Powell, C.J. (1996) Strain-specific enhancement or inhibition of coumarin hepatotoxicity in mice following pretreatment with two different liver enzyme-inducing agents. Fundam. appl. Toxicol, 34, 47-55 Cox, D., O Kennedy, R. Thornes, R.D. (1989) The rarity of liver toxicity inpatients treated with coumarin (1,2-benzopyrone). Hum. exp. Toxicol, 8, 501-506 Dexeus, E.H., Logothetis, C.J., Sella, A., Fitz, K., Amato, R., Reuben, J.M. Dozier, N. (1990) Phase II study of coumarin and cimetidine in patients with metastatic renal cell carcinoma. J. din. Oncol, 8, 325-329... 

BARBITURATES PROCARBAZINE t risk of hypersensitivity reactions in patients with brain tumours Strong correlation between therapeutic antiepileptic level and hypersensitivity reactions Consider using non-enzyme-inducing agents... 

Halothane also reduces liver blood flow during anesthesia, and this could increase the release of potentially hepatotoxic halothane metabolites. The role of reduced halothane metabolites and inorganic fluoride, which may covalently link to liver macromolecules, has been stressed in keeping with this hypothesis is the observation of halothane hepatitis in patients who simultaneously take enzyme-inducing agents, for example barbiturates (41) or rifampicin (42). 

Both patients were taking a non-enzyme-inducing agent (valproate and lamotrigine respectively), which probably resulted in higher serum tiagabine concentrations than those seen in enzyme-induced patients. 

TABLE 5.19 Major types of cytochrome P-450 enzyme inducing agent... 

The application of a metabolic activation system is recommended, since pollutants such as PAH are not genotoxic in their parent chemical form but are transformed during metabolism by enzymes of organisms. A commonly used system is the S-9 homogenate prepared from the liver of rats treated with enzyme inducing agents. 

A high serum yGT is not diagnostic of alcohol abuse. yGT is induced by a number of enzyme-inducing agents such as phenytoin and phenobarbitone which this boy was taking. 

Initial doses 4 mg/day is recommended and increased by 4 mg/day q 7 days until a usual maintenance dose of 32 to 56 mg/day given BID to QID if the drug is administered as add-on therapy with enzyme-inducing drugs. Initiate move slowly if non-enzyme-inducing agents are used concurrently. 

Endocrine Enzyme inducing agents, such as phenytoin, can increase the clearance rates of cortisol and synthetic glucocorticoids. 

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