An Animal And Clinical Study On Rectal Administration Of Mixed Soluble Preparation Of An Antipyretic With An Anticovulsant

【Objective】To select an ideal soluble antipyretic administered rectally for a further study to produce a powerful mixed formulation of antipyretic and anticonvulsant.【Methods】There were three antipyretics, including acetaminophen, ibuprofen and ketoprofen, which are common used by pediatrician, to be studied comparatively for their pharmacokinetics and pharmacodynamics of each drug with rectal and oral administration. (1)Comparison of pharmacodynamics: 64 Wistar rats were randomly assigned to the following four groups: normal control group; yeast-treated control group; oral administration group and rectal administration group. Rats were injected at dorsal site subcutaneously with a dose of 10ml/kg of 10% yeast suspension. The antipyretics were used respectively after three hours asincreased body temperature had been presented in all experimental rats. Rectal temperatures were taken before and every one hour after dosing in 8 hours. (2)Comparison of pharmacokinetics: 48 rabbits were randomly divided into oral administration group and rectal administration group. Blood samples were taken just before and 5, 15, 30, 60, 90, 120, 180, 240, 300, 360 minutes after dosing and all samples were assayed by HPLC. All of pharmacokinetic parametes in every group, such as blood concentration at each time point and Tlag,Tmax,Cmax,AUC, were collected and analysed comparativly.【Results】(1)Paracetamol: The Tlag and Tmax of paracetamol, when administered rectally, were significantly longer than that when administer- ed orally, the Cmax for rectal administration was only 42.0% of that for oral administration, and the relative bioavailability of the rectal administration, compared with the oral administration, was 60.1%. Its antipyretic effect after rectal administration was significantly weaker and shorter lasting than that after oral administration and the fever reduction was observed only in the first hour after dosing. (2)Ibuprofen and ketoprofen: Their Tlag and Tmax for oral and rectal administation were not significantly different. When administered rectally, the Cmax was 30% lower than that of oral administration, but the AUC was about 80% of that obtained after oral administration. Remarkable fever reduction had been observed since thefirst hour after dosing and lasted for eight hours either orally or rectally administered. The antipyretic efficacy for oral administration seemed to be potenter than that for rectal administration, but the difference was not significant statistically. (3)Compared with those for rectal ibuprofen and ketoprofen, the Tlag and Tmax for rectal paracetamol were significantly longer and the relative bioavailability was obviously lower. The antipyretic efficacy for rectal acetaminophen was more weaker and shorter lasting than those for rectal ibuprofen and ketoprofen which were not significant different.【Conclusions】(1)When administered rectally, the absorption of paracetamol was delayed and incomplete and irregular, and the antipyretic effect was more weaker and shorter lasting than that for oral administrtion. (2)The rectal absorption of ibuprofen and ketoprofen were rapid and complete which were comparable with that of oral dosing. Potent fever reduction and long lasting antipyretic efficacy were well demonstrated both after oral and after rectal administration with ibuprofen and ketoprofen. (3)For rectal administration, ibuprofen and ketoprofen were superior to paracetamol on their pharmacokinetics or pharmacodynamics. (4)Ibuprofen would be an ideal antipyretic drug to consist of a powerful mixed formulation with anticonvulsant according to the result as above and much less side effects of ibuprofen comparing with others.【Key words】paracetamol; ibuprofen; ketoprofen; solution; rectal administration...