Phenobarbital enzyme induction

Apart from monooxygenases, other enzymes concerned wih xenobiotic metabolism may also be induced. Some examples are given in Table 2.5. Induction of glucuronyl transferases is a common response and is associated with phenobarbital-type induction of CYP family 2. Glutathione transferase induction is also associated with this. A variety of compounds, including epoxides such as stilbene oxide and... 

Intake of various xenobiotics such as phenobarbital, PCBs, or certain hydrocarbons can cause enzyme induction. It is thus important to know whether or not an individual has been exposed to these inducing agents in evaluating biochemical responses to xenobiotics. Metabolites of certain xenobiotics can inhibit or stimulate the activities of xenobiotic-metabolizing enzymes. 

Whysner J, Ross PM, Williams GM (1996) Phenobarbital mechanistic data and risk assessment enzyme induction, enhanced cell proliferation, and tumor promotion. Pharmacol Ther 71 153-191... 

Enzymatic-metabolic activation (in part unknown)/phenobarbital-like promotion Hepatic enzyme induction, thyroid enzyme inhibition/axazepam, amobarbital, sulphonamides, thioureas Gastric secretory suppression, gastric atrophy induction (climetidine, omeprazole, butachlor... 

Phenobarbital is still used for the management of partial seizures, generalized tonic-clonic seizures and for the control of status epilepticus. However because of its low therapeutic index and the possibility of dependence, phenobarbital has largely been displaced by other anticonvulsants. For newborns phenobarbital is often the drug of first choice. If given together with sodium valproate the metabolism of phenobarbital may be inhibited while in combination with carbamazepine the serum concentrations of carbamazepine will be reduced due to enzyme induction by phenobarbital. 

Certain drugs induce the hepatic microsomal enzyme system i.e. enzyme induction, which decreases the effectiveness of other drugs, for example, if phenobarbital is suddenly discontinued without lowering the dosage of coumarin, severe hemorrhage can occur. 

Cyclosporin is metabolised by the hepatic cytochrome P-450 enzyme system, and enzyme induction by phenobarbital, phenytoin, carbamazepine, or rifampicin will drastically increase the clearance of cyclosporin. Concurrent administration of these drugs has caused rejection of transplanted organs. Conversely, the use of enzyme inhibitors, such as erythromycin or the azole antifungal agents, e.g. ketoconazole, will increase the blood concentrations of cyclosporin leading to an increased risk of toxic side effects. 

The response of an organism to a toxic compound may become modified after repeated exposure. For example, tolerance or reduced responsiveness can develop when a compound is repeatedly administered. This may be the result of increasing or decreasing the concentration of a particular enzyme involved or by altering the number of receptors. For example, repeated dosing of animals with phenobarbital leads to tolerance to the pharmacological response as a result of enzyme induction (see chap. 5). Conversely, tolerance to the hepa to toxic effect of a... 

Tolerance is the modification of the biological effect of a chemical as a result of repeated dosing. For example, repeated dosing with phenobarbital leads to a decrease in the anesthetic effect of the drug as a result of enzyme induction. Giving animals a small dose of carbon tetrachloride renders a second larger dose less toxic. This may be a result of induction of repair processes and destruction of cytochrome P-450 caused by the small first dose. 

Being one of the long-time standards in basic psychopharmacology, there are few major variants to the procedure apart from the kind of barbiturate employed. Several barbiturates undergo clear hepatic metabolism, for example pentobarbital and phenobarbital, thereby confounding interpretations because of pharmacokinetic and metabolic factors. Indeed, one modification of the method has been specifically employed to estimate enzyme induction in the liver as indicated by more rapid barbiturate metabolism. Animals given a pre-exposure to a test substance are then exposed to a standard dose of phenobarbital (80 mg/kg i.p.) 24 hours later and assessed for sleep duration. The presence or absence of a decrease in sleep duration is taken as an index of the hepatic enzyme induction produced by the test substance (Kushikata et al. 2003). 

Non-receptor related mechanisms Enzyme induction may occur via non-receptor related mechanisms. CYP2A6, although known to be induced by phenobarbital and rifampin, may involve mRNA stabilization. CYP2E1 induction may be a result of stabilization of mRNA and protein. 

Enzyme induction can be problematic with co-administration of benzodiazepines and rifampicin or certain anticonvulsants (phenobarbital, phenytoin, carbamaze-pine). However, despite enzyme stimulation, the net effect of adding these anticonvulsants can be augmentation of benzodiazepine-induced sedation. 

Contrary to these findings of decreased CarbE activity increasing the toxicity of many OPs, there are also data showing that increased CarbE activity can decrease toxicity of OPs. Activity of CarbE can be increased by about 80% after repeated administration of phenobarbital to rats and mice by a mechanism of enzyme induction which caused a decrease in soman and tabun toxicity by two-fold, while... 

TOEI type of enzyme induction (1) PB-type Phenobarbital inducer induction of cytochrome P450 lA (CYPIA). (2) MC-type 3-Methylcholanthrene type inducer induction of cytochrome P450 2B (CYP2B). (3) Mixed-type some of both PB- and MC-type inducers mixed CYP1A/CYP2B induction. 

PCN exposure to rats causes enzyme induction in the liver, kidney and lung [250-252]. Mixed-function oxygenases (MFO) are involved in the hydroxyla-tion of xenobiotica. The induction potency of a compound depends on the chlorination degree, substitution pattern and planarity of the molecule. The compounds 3-methylcholanthrene and phenobarbital induce two different... 

Anticonvulsants. Carbamazepine, phenobarbital and primidone accelerate warfarin metabolism (enzyme induction) the effect of phenytoin is variable. Clonazepam and sodium valproate are safe. 

Drugs. Antiepilepsy drugs, particularly phenytoin, primidone and phenobarbital, occasionally cause a macrocytic anaemia that responds to folic acid. This may be due to enzyme induction by the antiepileptics increasing the need for folic acid to perform hydroxylation reactions (see Epilepsy) but other factors such as reduced absorption may be involved. Administration of folic acid causes a recurrence of seizures in some patients. Some anti-malarials, e.g. pyrimethamine, may interfere with conversion of folates to the active tetrahydrofolic acid, causing macrocytic anaemia. Methotrexate, another folate antagonist, may cause a megaloblastic anaemia especially when used long-term for leukaemia, rheumatoid arthritis or psoriasis. 

Warfarin and Phenoharhital. Phenobarbital, by causing enzyme induction, can increase the rate of metabolism of warfarin. The result of this interaction is a decreased response to the anticoagulant and an increased risk of thrombus formation if the interaction is not recognized. 

Chronic treatment with phenobarbital, phenytoin, and carbamazepine is associated with reduced serum folate concentrations. Although megaloblastic anemia is rare, macrocytic changes in red cells are common in these patients. The fact that serum folate is not reduced by valproate and zonisamide, which do not induce liver enzymes, is consistent with the hypothesis that enzyme induction plays a role in the pathogenesis of folate deficiency (99). 

In addition to enzyme induction, phenobarbital can reduce dicoumarol absorption. 

Mazze Rl, Hitt BA, Cousins MJ. Effect of enzyme induction with phenobarbital on the in vivo and in vitro defluorination of isoflu-rane and methoxyflurane. J Pharmacol ExpTher 1974 90(3) 523-9. 

---