Carbamazepine (Fig. 3) is an anticonvulsant drug that is structurally similar to tricyclic antidepressants and is used in treatment of generalized tonic-clonic, partial, and partial-complex seizures. It was approved for treatment of epileptic patients in

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Fig. 3. Carbamazepine.

the USA in 1974 (approved for children over 6 years of age in 1979). Along with phenytoin, carbamazepine is one of the most widely used anticonvulsant drugs. It is also often used in combination therapy with tricyclic antidepressant drugs and can be used in the treatment of neuropathic pain. Like many other anticonvulsant drugs, the pharmacodynamic effects of carbamazepine are better correlated with serum or plasma concentrations rather than drug dosage. The proposed mechanism of action for carbamazepine is that of stabilizing the inactive state of voltage-gated sodium channels in the brain. The result is that brain cells are less excitable, and seizure activity is reduced. Side effects from drug levels exceeding the optimum therapeutic level include loss of coordination, drowsiness, and arrhythmia.

Early methods for monitoring of carbamazepine included GC, HPLC, or GC coupled with mass spectrometry (GC-MS) (18-20). However, most clinical laboratories currently use immunochemical methods for measuring concentrations of carbamazepine in blood (21). In chromatographic based methods, no significant interferences have been reported in the scientific literature with carbamazepine metabolites, but cross-reactivity of carbamazepine metabolites and structurally similar compounds may pose a problem in carbamazepine immunoassays. These include carbamazepine 10,11-epoxide, oxcarbazepine and its metabolites, as well as hydroxyzine and its metabolites.

The most important metabolite of carbamazepine is carbamazepine 10, 11-epoxide (Fig. 4), which possesses similar pharmacodynamic activity to its parent drug. Carbamazepine is extensively metabolized by the cytochrome P450 enzyme system (CYP3A4 and CYP2C8) to form the epoxide metabolite (22). At steady state, pre-dose concentrations of carbamazepine epoxide should be approximately 20-25% of the parent drug concentration. However, when other drugs are coadministered, the concentration of carbamazepine epoxide can reach much higher levels at steady state because of drug-drug interactions. Quetiapine increases concentrations of epoxide (epoxide to carba-mazepine ratio may increase three- to fourfold) and levels of epoxide returned to normal after discontinuation of quetiapine. Quetiapine may inhibit epoxide hydrolase that


Fig. 4. Carbamazepine 10, 11-epoxide.

transforms carbamazepine-10, 11-epoxide to carbamazepine 10, 11-trans-dio\ as well as glucuronidation of trans-diol (23). Valproic acid also inhibits the glucuronidation of carbamazepine 10, 11-trans-diol and probably inhibits the conversion of carbamazepine 10, 11-epoxide to this trans-diol thus increasing carbamazepine 10, 11-epoxide concentrations relative to carbamazepine dose in patients receiving both carbamazepine and valproic acid compared with in patients receiving carbamazepine alone (24,25). Valpromide, valnoctamide, and progabide also inhibit epoxide hydrolase thus causing valproic toxicity because of increases in concentrations of carbamazepine 10,11-epoxide. Inhibition of carbamazepine metabolism and elevation of plasma carba-mazepine to potential toxic concentrations can also be due to cotherapy with stiripentol, remacemide, acetazolamide, macrolide antibiotics, isoniazid, metronidazole, verapamil, diltiazem, cimetidine, danazol, or propoxyphene (26).

Phenytoin, phenobarbital, and primidone accelerate metabolism of carbamazepine by inducing cytochrome P450 (CYP) 3A4 and reduce plasma concentrations of carbamazepine to clinically significant levels (26). Serum carbamazepine concentration to dose ratios in patients with carbamazepine polytherapy were decreased while carbamazepine 10, 11 epoxide and trans 10-11-dihydroxy-10,11-dihydro-carbamazepine concentrations were increased. The authors concluded that phenytoin has a potent induction effect on carbamazepine epoxidase whereas phenobarbital is a moderate inducer (27). In contrast, Pereira et al. (28) reported that lamotrigine did not alter plasma concentrations of carbamazepine significantly. Nevertheless, authors strongly recommended TDM because of narrow therapeutic range of both drugs. There is also no pharmacokinetic interaction between oxcarbazepine and lamotrigine (29).

Carbamazepine-indinavir interaction has clinical significance. The indinavir (a protease inhibitor) plasma concentrations in a patient was decreased significantly when carbamazepine was introduced in the drug regime Carbamazepine is a potent inducer of CYP3A enzyme system whereas indinavir is a substrate for that enzyme.

A low-dose carbamazepine (200 mg per day) and the usual dose of indinavir (800 mg q8h) in this patient resulted in carbamazepine concentration within therapeutic range but indinavir concentration was significantly reduced. Authors concluded that concomitant use of carbamazepine and indinavir may cause failure of antiretroviral therapy because of insufficient indinavir plasma concentration, and drugs other than carbamazepine should be considered in prevent this interaction (30).

The cross-reactivity of carbamazepine epoxide in carbamazepine immunoassays has been investigated across numerous analytical platforms (8,21,31-33). The cross-reactivity of carbamazepine 10, 11-epoxide with carbamazepine may vary from 0.0% (Vitros, Rochester, NY, USA) to 93.6% (Dade Behring) with many immunoassays exhibiting low (EMIT; 0.4%, Technicon immuno-1; 1.6% ACS:180; 3.8%, Beckman Synchron; 7.6%) to moderate (Roche Cobas Integra; 10.4%, BDI Opus/plus/magnum; 17.2%, Abbott TDX; 20.8%, Dade ACA; 44.2%) (34). Therefore, authors concluded that Dade Behring's PETINIA assay has significant cross-reactivity with carbamazepine 10,11-epoxide and provides an estimate of both the parent drug and the metabolite (34). Currently, there is no commercially available immunoassay for measuring carbamazepine 10, 11-epoxide concentration. However, both HPLC and HPLC combined with mass spectrometric methods have been reported in the literature for simultaneous determination of both carbamazepine and its active metabolites (also see Chapter 3).

Oxcarbazepine (Fig. 5) is a structurally similar drug to carbamazepine that is used in the treatment of epilepsy. In some cases, both drugs and their metabolites may both be present in patients who are transitioning from one therapeutic regimen to the other. In a study of whether oxcarbazepine or its metabolites cross-reacted with an EMIT carbamazepine assay, it was shown that from a clinical perspective that only the 10-hydroxy-10,11-dihydro-carbamazepine metabolite of oxcarbazepine had any significant cross-reactivity with the assay whereas there was no significant interference from oxcarbazepine (35).

Another study reporting case reports of falsely elevated carbamazepine results associated with the presence of hydroxyzine (Fig. 6)—a benzhydrylpiperazine antihistamine—in the specimen (36). Hydroxyzine is a commonly prescribed first

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