Oxcarbazepine Therapy Research Articles

Pharmacokinetics of oxcarbazepine and carbamazepine in human placenta.

To study the transfer and metabolism of oxcarbazepine (OCBZ) and 10-hydroxy-10,11-dihydrocarbamazepine (10-OH-CBZ) and carbamazepine (CBZ) metabolism and its possible induction in human placenta. A dual recirculating human placental perfusion system, blood sampling, high performance liquid chromatography (HPLC), reverse transcriptase-polymerase chain reaction (RT-PCR), and enzyme assays. OCBZ was metabolized into 10-OH-CBZ in five human placental cotyledons perfused for 2 h in a dual recirculating perfusion system. The same metabolite was found by HPLC in three sample pairs of maternal and cord blood taken during delivery from patients on OCBZ therapy. In all of the clinical samples, 10,11-trans-dihydroxy-10,11-dihydrocarbamazepine (10,11-D) was also found, but not in the perfusions. In addition, 10-OH-CBZ was not metabolized in the placental perfusions. The transfer of OCBZ through the perfused placentas was quicker than the transfer of antipyrine, while the transfer of 10-OH-CBZ was slower. Both OCBZ and 10-OH-CBZ also accumulated in placental tissue. CBZ metabolism was studied in three perfusions using placentas from mothers on CBZ therapy. No metabolism could be detected in the perfused placentas, while metabolites were found in both maternal and cord blood of the same mothers. Another series of placentas of mothers on CBZ therapy did not differ significantly from the placenta of a healthy mother as to CYP activities or the level of CYP3A4 mRNA. OCBZ is metabolized into 10-OH-CBZ to some extent in human placenta in vitro, suggesting that the placenta also participates in the metabolism of OCBZ in vivo. On the contrary, the placenta does not participate in the metabolism of CBZ. No induction of placental CBZ metabolism in vitro can be detected after maternal CBZ treatment during pregnancy.

Oxcarbazepine: pharmacokinetic interactions and their clinical relevance.

Antiepileptic drug (AED) interactions are a common problem during epilepsy treatment. Oxcarbazepine (OCBZ) is a keto homologue of carbamazepine (CBZ) with a completely different metabolic profile. In humans, the keto group is rapidly and quantitatively reduced to form a monohydroxy derivative (MHD), which is the main active agent during OCBZ therapy. MHD is eliminated by renal excretion, glucuronidation and, marginally, by hydroxylation to a diol derivative. This metabolic profile, and in particular the limited involvement of oxidative microsomal enzymes, suggests that OCBZ may have fewer drug interactions compared with traditional AEDs. This possibility has been investigated in experimental studies and, retrospectively, in data obtained from clinical trials. The capacity of OCBZ to induce microsomal enzymes of the P-450 family has mostly been examined by use of antipyrine and CBZ kinetics as markers. The results suggest that OCBZ has little enzyme inducing capacity. In clinical trials in which OCBZ was substituted for CBZ, plasma concentrations of concomitant AEDs were increased, possibly as a consequence of total or partial de-induction. OCBZ interference with other drugs has been evaluated for warfarin, felodipine, and oral contraceptives, three medications strongly influenced by enzyme-inducing AEDs. OCBZ does not modify the anticoagulant effect of warfarin, whereas some reduction in felodipine concentration and a clinically significant reduction of contraceptive drug levels and efficacy were observed. Polytherapy with established AEDs does not significantly modify OCBZ disposition (MHD kinetics); however, available information is not extensive. Finally, the action on OCBZ kinetics of a group of drugs (verapamil, cimetidine, erythromycin, dextropropoxyphene, and viloxazine) known to inhibit the metabolism of some AEDs has been studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyponatremia associated with carbamazepine and oxcarbazepine therapy: a review.

Hyponatremia, an electrolyte disturbance usually without clinical significance, may sometimes lead to serious complications when overlooked or not treated appropriately. One cause of hyponatremia, the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, has been associated with some drugs, including carbamazepine (CBZ). Because of its antidiuretic effects, CBZ has been used successfully to treat diabetes insipidus centralis. Possible mechanisms for the antidiuretic effects of CBZ have been proposed. Altered sensitivity to serum osmolality by the hypothalamic osmoreceptors appears likely, but an increased sensitivity of the renal tubules to circulating ADH cannot be excluded. CBZ has led to hyponatremia in patients with epilepsy, neuralgia, mental retardation, and psychiatric disorders with a frequency varying from 4.8 to 40%. Oxcarbazepine (OCBZ), which is structurally related to CBZ, has shown similar hyponatremic effects, but whether hyponatremia occurs more often than with CBZ is not yet clear. Experience with OCBZ is still limited, and there is no definite explanation for a possible difference in antidiuretic potency. Most patients with CBZ/OCBZ-induced hyponatremia are asymptomatic. In rare cases, water intoxication has been reported, necessitating treatment discontinuation.

In vitro lymphocyte proliferation by carbamazepine, carbamazepine-10, 11-epoxide, and oxcarbazepine in the diagnosis of drug-induced hypersensitivity

In vitro lymphocyte proliferation induced by carbamazepine (CBZ) was evaluated in nine patients with hypersensitivity to this drug. Lymphocytes from all hypersensitive patients responded by significantly enhanced DNA synthesis to CBZ when patients were compared with 33 tested control subjects. However, lymphocytes from five of six hypersensitive patients were not stimulated by carbamazepine-10, 11-epoxide, and oxcarbazepine (OXC), and this was confirmed clinically in two CBZ hypersensitive patients with OXC therapy. The results indicate that OXC may be suitable as an alternative therapy in some patients with CBZ hypersensitivity.

Use of saliva for monitoring oxcarbazepine therapy in epileptic patients.

The utility of saliva sampling in monitoring oxcarbazepine therapy has been assessed in 17 epileptic outpatients treated with a mean dose 22.7 mg/kg/d for 19-411 days, i.e. at steady-state. Blood was collected before the morning dose measurement of the plasma 10-OH-carbazepine concentration and determination of the protein bound fraction. Immediately after blood sampling resting saliva and saliva produced after a masticatory stimulus were collected. Using equilibrium dialysis and an ultrafiltration technique the protein binding of 10-OH-carbazepine was found to be 40% and 45%, respectively. When the degree of protein binding was expressed as the ratio between the corresponding saliva and plasma concentrations of 10-OH-carbazepine, the concentration in resting saliva indicated that no drug was bound to plasma protein, whereas the use of stimulated saliva suggested a protein-bound fraction of 35%. The concentration in stimulated saliva reflects the free fraction of 10-OH-carbazepine, but regression analysis of paired salivary and plasma values showed that the prediction of plasma concentrations from levels in saliva is uncertain. This, together with the low degree of plasma protein binding, leads to the conclusion that it would be preferable to monitor total plasma concentrations if therapeutic drug monitoring of oxcarbazepine were to prove essential in epileptic patients.