Phenytoin with hepatic microsomal

Reduced ethinyl estradiol concentrations have been associated with concomitant use of substances that induce hepatic microsomal enzymes, such as rifampin, rifabutin, barbiturates, phenylbutazone, phenytoin sodium, griseofulvin, topiramate, some protease inhibitors, modafinil, and possibly St. John s wort ... 

Long-term anticonvulsive therapy with diphenylhydantoin or phenobarbital is known to cause osteomalacia by influencing calcium metabolism (24,25). Alteration in the metabolism of vitamin D, presumably secondary to induction of hepatic microsomal enzymes, leads to the calcium and bone abnormalities (26). Patients on anticonvulsive therapy with phenytoin exhibit a decrease in serum 25-hydroxyvitamin D (27). Adequate dietary amounts of vitamin precursors or microsomal enzyme stimulators might prevent these effects of long-term therapy. 

Several reports have described ticlopidine-induced phenytoin toxicity with increased serum phenytoin concentrations (33-36). Data obtained in vitro using hepatic microsomal preparations have shown that ticlopidine inhibits the activity of CYP2C19 (37). 

Doxycycline at recommended doses does not accumulate significantly in patients with renal failure and thus is one of the safest of the tetracyclines for use in patients with renal impairment. The drug is excreted in the feces. Its half-life may be significantly shortened by concurrent therapy with barbiturates, phenytoin, rifampin, or other inducers of hepatic microsomal enzymes. 

Although a less potent inducer of CYPs than rifampin, rifabutin does induce hepatic microsomal enzymes, with its administration decreasing the half-life of a number of different compounds, including zidovudine, prednisone, digi-toxin, quinidine, ketoconazole, propranolol, phenytoin, sulfonylureas, and warfarin. It has less effect than does rifampin on serum levels of indinavir and nelfinavir. 

Carbamazepine induces hepatic microsomal enzymes that can decrease the steady-state plasma levels of phenothiazines (reported mainly with chlorpromazine, fluphenazine, and perphenazine). Chlorpromazine and thioridazine may increase the serum levels of phenytoin due to its inhibition of hepatic mono-oxygenase activities. 

CAUTION. Phenytoin. (anticonvulsant) and phenobarbital (long-acting barbiturate) can induce hepatic microsomal enzymes and thereby retard the half-life significantly and, therefore, ultimately interfering with the prevalent efficacy of the drug . 

Elevated activities of GGT are found in the sera of patients with alcoholic hepatitis and in the majority of sera from people who are heavy drinkers. Increased concentrations of the enzyme are also found in serum of subjects receiving anticonvulsivant drugs such as phenytoin and phe-nobarbital. Such an increase of GGT activity in serum may reflect induction of new enzyme activity by the action of the alcohol and drugs and/or their toxic effects on microsomal structures in liver cells. 

In other instances, a nontoxic parent compound is transformed by CYP into a reactive metabolite that is toxic to the mitochondria. This is seen with acetaminophen, which is transformed by CYP2E1 to the chemically reactive, N-acetyl-p-benzoquinone imine. The hepatic toxicity of acetaminophen is increased in alcoholics (Seef et al. 1986). Ethanol abuse increases CYP2E1 in the endoplasmic reticulum and in the mitochondria (Robin et al. 2005). The mitochondrial localization of CYP2E1 may lead to the in situ generation of reactive metabolites of acetaminophen in the mitochondria, where the metabolite may trigger MPT (Weis et al. 1992 Masubuchi et al. 2005). Mitochondria also contain other inducible CYPs, such as CYPlAl and CYP2B1 (Anandatheerthavarada et al. 1997 Sepuri et al. 2007). The concomitant administration of CYP-inducers, phenobarbital or phenytoin increases the hepatotoxicity of valproic acid, which is transformed by microsomal and mitochondrial CYPs and then p-oxidation enzymes into a reactive... 

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