Relative bioavailability, metabolism and tolerability of rectally administered oxcarbazepine suspension.
OBJECTIVE
Maintenance of effective drug concentrations is essential for adequate treatment of epilepsy. Some antiepileptic drugs can be successfully administered rectally when the oral route of administration is temporarily unavailable. Oxcarbazepine is a newer antiepileptic drug that is rapidly converted to a monohydroxy derivative, the active compound. This study aimed to characterise the bioavailability, metabolism and tolerability of rectally administered oxcarbazepine suspension using a randomised, crossover design in ten healthy volunteers.


METHODS
Two subjects received 300 mg doses of oxcarbazepine suspension via rectal and oral routes and eight received 450 mg doses. A washout period of at least 2 weeks elapsed between doses. The rectal dose was diluted 1:1 with water. Blood samples and urine were collected for 72 hours post-dose. Adverse effects were assessed at each blood collection time-point using a self-administered questionnaire. Plasma was assayed for oxcarbazepine and monohydroxy derivative; urine was assayed for monohydroxy derivative and monohydroxy derivative-glucuronide. Maximum plasma concentration (C(max)) and time to reach C(max) (t(max)) were obtained directly from the plasma concentration-time curves. The areas under the concentration-time curve (AUCs) were determined via non-compartmental analysis. Relative bioavailability was calculated and the C(max) and AUCs were compared using Wilcoxon signed-rank tests.


RESULTS
Mean relative bioavailability calculated from plasma AUCs was 8.3% (SD 5.5%) for the monohydroxy derivative and 10.8% (SD 7.3%) for oxcarbazepine. Oxcarbazepine and monohydroxy derivative C(max) and AUC values were significantly lower following rectal administration (p < 0.01). The total amount of monohydroxy derivative excreted in the urine following rectal administration was 10 +/- 5% of the amount excreted following oral administration. Oral absorption was consistent with previous studies. The most common adverse effects were headache and fatigue with no discernible differences between routes.


CONCLUSIONS
Monohydroxy derivative bioavailability following rectal administration of oxcarbazepine suspension is significantly lower than following oral administration, most likely because of poor oxcarbazepine water solubility. It is unlikely that adequate monohydroxy derivative concentrations can be achieved with rectal administration of diluted oxcarbazepine suspension.
Clemens
Pamela L
PL
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
Cloyd
James C
JC
Kriel
Robert L
RL
Remmel
Rory P
RP
D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019540:Area Under Curve; D001682:Biological Availability; D002220:Carbamazepine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D018592:Cross-Over Studies; D004333:Drug Administration Routes; D006801:Humans; D008875:Middle Aged; D000078330:Oxcarbazepine; D012007:Rectum
D000927:Anticonvulsants; D002220:Carbamazepine; D000078330:Oxcarbazepine