Effects of semi-solidification of enteral nutrients on the pharmacokinetic behavior of orally administered carbamazepine in rats.

The use of semi-solid enteral nutrients plays an extremely important role in accurate nutrition management. In the present study, we compared the pharmacokinetic profile of orally administered carbamazepine (CBZ) in rats treated with liquid RACOL®, semi-solid RACOL®, and HINE E-gel®, which are enteral nutrients marketed in Japan. Since liquid and semi-solid formulations are both marketed in Japan for RACOL®, liquid RACOL® was orally administered to control rats. The serum concentration of CBZ at each sampling point was lower in the semi-solid RACOL®-treated group than in the liquid RACOL®-treated group. No significant differences were observed in the pharmacokinetic behavior of CBZ between the semi-solid RACOL®-treated and HINE E-gel®-treated groups. Regarding pharmacokinetic parameters, the impact of the area under the curve (AUC0→5h) was the liquid RACOL® group > the semi-solid RACOL® group ≈ the HINE E-gel® group. Therefore, we concluded that serum concentrations of CBZ were lower when concurrently treating with semi-solid enteral nutrients than when simultaneously processing liquid enteral nutrients.

Alterations in Pharmacokinetics of Orally Administered Carbamazepine in Rats Treated with Sodium alginate: Possible Interaction between Therapeutic Drugs and Semi-solid Enteral Nutrients.

OBJECTIVE: The use of enteral nutrients plays an extremely important role in accurate nutrition management. Sodium alginate (SA) is frequently used for the semi-solidification of enteral nutrients. In the present study, we investigated whether the pharmacokinetic profile of orally administered carbamazepine (CBZ) is altered by a treatment with SA immediately before and after dosing of the drug. Furthermore, the adsorption effects of SA on CBZ were examined using an in vitro analysis. METHOD: SA was orally administered to rats just before and immediately after CBZ dosing. The CBZ concentration profile following its oral administration was analyzed by a non-compartmental method. The adsorption of CBZ onto SA was evaluated after centrifugation using an ultrafiltration device. FINDINGS: The serum concentration of orally administered CBZ at each sampling point was reduced by the treatment with SA, and the extent of the decrease observed in the concentration of CBZ was larger when SA was ingested immediately after administration of the drug, which was consistent with the alteration observed in the value of the area under the curve (AUC). No significant differences were noted in the elimination rate at the terminal phase (ke) among the groups. In the in vitro assay, CBZ was adsorbed by SA in the solution used to reflect fluid in the intestinal tract. CONCLUSIONS: The pharmacological efficacies of CBZ might be reduced by SA through the pharmacokinetic interactions, and that the careful attention should be paid to the timing of administration of CBZ and semi-solid enteral nutrients.

In vivo antitumor activity of a novel sulfonamide, HMN-214, against human tumor xenografts in mice and the spectrum of cytotoxicity of its active metabolite, HMN-176.

The cytotoxic effects of HMN-176 ((E)-4-[[2-N-[4-methoxybenzenesulfonyl] amino] stilbazole] 1-oxide; a newly synthesized compound, were evaluated and compared with those of the clinically used antitumor agents cis-platinum, adriamycin, etoposide, taxol, and vincristine in 22 human tumor cell lines isolated from various organs. HMN-176 exhibited potent cytotoxicity with IC(50) values in the nM range, and the variance of its cytotoxic efficacy was remarkably small. Drug-resistant cell lines also showed low cross-resistance to HMN-176 corresponding to overall resistance indices of less than 14.3. HMN-214 was synthesized as an oral prodrug because of the poor oral absorption of HMN-176 itself. Pharmacokinetic studies showed that HMN-214 was an acceptable oral prodrug of HMN-176. In the in vivo analysis of the schedule-dependency of HMN-214, the repeated administration for over 5 days elicited potent antitumor activity, as expected from the exposure-dependency of the cytotoxicity of HMN-176 and from the cytometric studies. The antitumor activity of HMN-214 against human tumor xenografts was equal or superior to that of clinically available agents, including cis-platinum, adriamycin, vincristine, and UFT without severe toxicity such as neurotoxicity. Because of its good activity in preclinical trials, HMN-214 has entered Phase I clinical trials in the USA.