Evaluation of cytochrome P450 inductions by anti-epileptic drug oxcarbazepine, 10-hydroxyoxcarbazepine, and carbamazepine using human hepatocytes and HepaRG cells.

Anti-epileptic drug oxcarbazepine is structurally related to carbamazepine, but has reportedly different metabolic pathway. Auto-induction potentials of oxcarbazepine, its pharmacologically active metabolite 10-hydroxyoxcarbazepine and carbamazepine were evaluated by cytochrome P450 (CYP) 1A2, CYP2B6 and CYP3A4 mRNA levels and primary metabolic rates using human hepatocytes and HepaRG cells. For the CYP1A2 the induction potential determined as the fold change in mRNA levels was 7.2 (range: 2.3-11.5) and 10.0 (6.2-13.7) for oxcarbazepine and carbamazepine, respectively, while 10-hydroxyoxcarbazepine did not induce. The fold change in mRNA levels for CYP2B6 was 11.5 (3.2-19.3), 7.0 (2.5-10.8) and 14.8 (3.1-29.1) for oxcarbazepine, 10-hydroxyoxcarbazepine and carbamazepine, respectively. The fold change for CYP3A4 induction level by oxcarbazepine, 10-hydroxyoxcarbazepine and carbamazepine was 3.5 (1.2-7.4), 2.7 (0.8-5.7) and 8.3 (3.5-14.5), respectively. The data suggest lower induction potential of oxcarbazepine and 10-hydroxyoxcarbazepine relative to carbamazepine. The results in HepaRG cells showed similar trend as the human hepatocytes. After incubation for 72 h in hepatocytes and HepaRG cells, auto-induction was evident for only carbamazepine metabolism. The 10-keto group instead of double bond at C10 position is evidently a determinant factor for limited auto-induction of P450 enzymes by oxcarbazepine.

Lymphatic absorption of subcutaneously administered proteins: influence of different injection sites on the absorption of darbepoetin alfa using a sheep model.

The relative contribution of the lymph and blood in the absorption of darbepoetin alfa (DA) from different s.c. injection sites was determined using a central lymph-cannulated sheep model. DA was administered to parallel groups either as a bolus i.v. injection (0.5 mug/kg) into the jugular vein or as a bolus s.c. injection (2 mug/kg) into the interdigital space, the abdomen, or the shoulder. In the lymph-cannulated groups, the thoracic lymph duct was cannulated for continuous collection of central lymph, and blood samples were periodically collected via the jugular vein in all the groups. The concentration of DA in serum and lymph was determined by enzyme-linked immunosorbent assay. The total fraction of the dose reaching the systemic circulation and the fractions absorbed via the lymph and the blood were determined. A pharmacokinetic model was constructed to simultaneously fit the data from all the treatment groups. Absorption was essentially complete for all three injection sites in non-lymph-cannulated s.c. groups, but the rates of absorption differed significantly. Based on the modeling results for the lymph-cannulated groups, the lymphatics represented the predominant absorption route for both the interdigital (90 +/- 1%) and the abdomen (67 +/- 9%) injection sites. Fluorescein isothiocyanate dextran visualization studies revealed that the lymph draining the shoulder injection site entered the thoracic lymph duct distal to the point of cannulation, effectively precluding collection of thoracic lymph from this site. For that reason, the contribution of the lymphatics following injection in the shoulder could not be determined using these cannulation procedures.