Carbamazepine pharmacokinetics

Burstein AH, Horton RL, Dunn T, Alfaro RM, Piscitelli SC, Theodore W. Lack of effect of St John s Wort on carbamazepine pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 2000 68(6) 605-612. 

Erythromycin can cause acute carbamazepine intoxication, probably by inhibiting its hepatic metabolism (63). Erythromycin may also directly inhibit the conversion of carbamazepine to its epoxide. In a controlled study of the effects of eiythromycin on carbamazepine pharmacokinetics in healthy volunteers, the clearance of a single dose of carbamazepine was reduced by 19% during erythromycin treatment (64). In contrast, the single-dose pharmacokinetics of phenytoin were not affected by erythromycin (65,66). After withdrawal of the macrolide, carbamazepine concentrations quickly return to normal (67). If co-administration of erythromycin and carbamazepine cannot be avoided, a dosage reduction of... 

Hidaka, M., Okumura, M., Fujita, K., Ogikubo, T., Yamasaki, K., Iwakiri, T., Setoguchi, N., and Arimori, K. (2005) Effects of pomegranate juice on human cytochrome P450 3A (CYP3A) and carbamazepine pharmacokinetics in rats. Drug Metab. Dispos. 33 (5), 644-648. 

St John s wort modestly increased the clearance of single-dose carbamazepine, but had no effect on multiple-dose carbamazepine pharmacokinetics. Carbamazepine does not appear to significantly affect the pharmacokinetics of hypericin or pseudohypericin (constituents of St John s wort). St John s wort is predicted to reduce the blood levels of phenytoin and phenobar-bital, but this awaits clinical confirmation. 

Daltxm MI, Powell IR, Messenheimer JA The influence of cimetidine cn sir le-dose carbamazepine pharmacokinetics. Epilepsia (1985) 26, 127-30. 

Marsden JR. Effect of isotretinoin on carbamazepine pharmacokinetics. BrJ Dermatol 9ZZ) 119,403-4. 

Ragueneau-Majlessi I, Levy RH, Bergen D, Garnett W, Rosenfeld W, Mather G, Shah J, Grundy JS. Carbamazepine pharmacokinetics are not affected by zonisamide in vitro mechanistic study and in vivo clinical study in epileptic patients. Epilepsy Res ( 004) 62, 1-11. 

The effect of alcohol addiction on carbamazepine pharmacokinetics and the severity of drug intoxication have been evaluated in 158 carbamazepine intoxicated patients (76 non-alcohol-dependent and 82 alcohol-dependent) [134 ]. The level of unconsciousness depended on carbamazepine concentration and anticholinergic toxic syndrome was more common in alcohol-dependent than non-alcohol-dependent patients. The average half-life of carbamazepine was 42 hours in non-addicted epileptics, 44 hours in alcohol-dependent patients during abstinence, and 39 hours in intoxicated patients. 

Many authors reported poor elimination of antiepileptic drug carbamazepine [6,13,17,49, 54]. Pharmacokinetic data indicate that only 1-2% of carbamazepine is excreted unmetabolized. However, glucuronide conjugates of carbamazepine can presumably be cleaved in the sewage, and thus increase its environmental concentrations [51]. This is confirmed by its high ubiquity in the enviromnent at concentration levels of several hundred nanograms per liter in different surface waters. Due to its recalcitrant nature, it can be used as anthropogeiuc marker for the contamination of aquatic environment. 

C. Comaggia, S. Gianetti, D. Battino, T. Granato, A. Romeo, F. Viani, and G. Limido, Comparative pharmacokinetic study of chewable and conventional carbamazepine in children, Epilepsia, 34, 158 (1993). 

All products have carbamazepine as active ingredients. Retard is slow release formulations. The products have different pharmacokinetics and are not bioequivalent. 

Little is known as yet about the pharmacokinetics of carbamazepine in humans although preliminary reports suggest slow absorption (M21) and marked variations in blood levels during a day in some subjects (M15). Blood levels varying from trace quantities to 12 /ig/ml have been found in patients taking 400-1000 mg daily (P3), but no relation between the level observed and the dose was apparent. In the studies so far published carbamazepine blood levels have not correlated with seizure control (P3), but all the subjects wore receiving additional anticonvulsant drugs. 

D6 - Tolterodine is not expected to influence the pharmacokinetics of drugs that are metabolized by cytochrome P450 2D6, such as flecainide, vinblastine, carbamazepine, and tricyclic antidepressants. 

The macrolide antibacterials (including erythromycin, clarithromycin and telithromycin) are often implicated in interactions, most frequently as a result of inhibition of the CYP3A4 enzyme system in the liver and enterocytes. Erythromycin inhibits the metabolism of carbamazepine, ciclosporin and theophylline significant increases in serum levels and features of toxicity have been documented. Careful clinical and pharmacokinetic monitoring are required in a patient taking any of these drugs who requires concomitant erythromycin. 

Battino D, Crod D, Rossini A, et al. Serum carbamazepine concentrations in elderly patients a case-matched pharmacokinetic evaluation based on therapeutic drug monitoring data. Epilepsia 2003 44 923-929. 

Carbamazepine (CBZ) and divalproex sodium (DVP) are the most common anticonvulsant agents prescribed for adult BD (Bowden et ah, 1994) Post et ah, 1998b) and pediatric epileptic disorders (Trimble, 1990 Dunn et al., 1998). As a consequence of their documented efficacy in these populations, their use has been extended to pediatric behavioral and mood disorders (Biederman et ah, 1998). We review here their mechanisms of action, pharmacokinetics, side effects, and pediatric uses. The multiple cytochrome P450 (CYB)-mediated potential drug interactions of CBZ and DVP are not covered in detail in this chapter. For a comprehensive review of this subjects the reader is referred to a recent publication by Flockhart and Oesterheld (2000). 

Quetiapine is metabolized by hepatic CYP 3A3/4. Concurrent administration of cytochrome P450-inducing drugs, such as carbamazepine, decreases blood levels of quetiapine. In such circumstances, increased doses of quetiapine are appropriate. Quetiapine does not appreciably affect the pharmacokinetics of other medications. Pharmacodynamic effects are expected if quetiapine is combined with medications that also have antihistaminic or a-adrenergic side effects. Because of its potential for inducing hypotension, quetiapine also may enhance the effects of certain antihypertensive agents. 

Antipsychotics. Clear guidelines for measuring therapeutic serum concentrations of antipsychotics have not yet been established. There may, however, be specific situations in which they may be of value (e.g., monitoring of haloperidol [HPDL] levels might be useful in patients on concurrent carbamazepine therapy because the latter agent can substantially reduce serum HPDL concentrations). These issues are discussed in greater detail in the Pharmacokinetics/Plasma Level section in Chapter 5. 

Spina E, Pisani F, Perucca E. Clinically significant pharmacokinetic drug interactions with carbamazepine. An update. Clin Pharmacokinei 1996 31 198-214. 

Because most antidepressants require oxidative metabolism as a necessary step in their elimination, they can be the target of a pharmacokinetic drug-drug interaction, as well as the cause. The CYP enzymes mediating the biotransformation of the various antidepressants are also shown in Table 7-30. CYP 1A2 and 3A3/4 are induced by anticonvulsants such as barbiturates and carbamazepine. As expected, coadministration of these anticonvulsants has been shown to lower plasma levels of TCAs and would be predicted to have the same effect on nefazodone, sertraline, and venlafaxine. 

Bertilsson L, Tomson T. Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11-epoxide. Clin Pharmacokinei 1986 11 177-198. 

GFJ has been shown to increase the exposure of carbamazepine (175), cisapride (176-179), fluvoxamine (184), losartan (188), methadone (189), scopolamine (191), and sertraline (192). However, only the interaction of GFJ with carbamazepine and cisapride seems to be clinically relevant. No alteration in exposure was observed for clozapine (180,181), heophylline (195), halo-peridol (196), and omeprazole (190). Reports of increased pharmacokinetic parameters of clozapine, theophylline, and haloperidol suggest that an interaction is unlikely to be clinically relevant. Contradicting results were reported for itraconazole (185-187), digoxin (75,183), and sildenafil (193,194). An increased effect on concomitant use of diclofenac and GFJ was observed in rats (182). Overall, the clinical relevance for this drug class appears to be low. 

Feldmann, K. F., Brechbuhler, S., Faigle, J. W., Imhof, P. Pharmacokinetics and metabolism ofGP47 680, a compound related to carbamazepine, in animals and man, in Advances in epileptology 1978, edited by H. Meinardi, A. J. Rowan, 290-294, Amsterdam Swets Zeitlingerr BV. 

---