Vree T B, Dammers E, Exler P S, Sörgel F, Bondesen S, Maes R A
Institute for Anaesthesiology, Academic Hospital Nijmegen Sint Radboud, The Netherlands.
Int J Clin Pharmacol Ther. 2000 Nov;38(11):514-22. doi: 10.5414/cpp38514.
The aim of this investigation was to identify which part of a dose mesalazine is acetylated by enzymes in the gut wall during the absorption process, and which part by the liver enzymes after absorption.
This study was based on data from four bioequivalence studies of different formulations of tablets (gastro-resistant single dose 500 mg (n = 24) and prolonged-release tablets (single dose 1000 mg, n = 18; multiple dose 1000 mg t.i.d. six days n = 28), suppositories (single 500 mg dose, n = 24) and a study with two i.v. administrations of 100 and 250 mg mesalazine (n = 6). In total, 200 administrations were carried out and plasma concentration-time curves obtained and analyzed. There was a large variability in the absorption of mesalazine for all formulations. The plasma concentration-time curves of parent drug and metabolite acetylmesalazine run nearly parallel, independent of the formulation and the dose. Plasma and urine mesalazine and acetylmesalazine concentrations were determined according to validated methods using HPLC analysis with coulometric or mass-spectrometric detection.
As a result of the large variations in release and absorption of mesalazine in the pharmaceutical formulations and administrations, it was possible to demonstrate that acetylation occurs in the gut wall and in the liver. By comparing oral and rectal data to intravenous data, it was possible to indicate where (and to what extent) acetylation occurs in the gut wall, in the liver, or both. Rectal administration of a mesalazine suppository and intravenous administration results in hepatic acetylation. Oral administrations of mesalazine results in both gut wall and hepatic acetylation. Acetylation by the gut wall amounts to 30% of the dose for gastroresistant tablets and to 40% of the dose for prolonged-release tablets.
本研究旨在确定美沙拉嗪剂量的哪一部分在吸收过程中被肠壁中的酶乙酰化，以及哪一部分在吸收后被肝脏酶乙酰化。
本研究基于四项不同片剂剂型（耐胃酸单剂量500mg（n = 24）和缓释片（单剂量1000mg，n = 18；多剂量1000mg，每日三次，共六天，n = 28））、栓剂（单剂量500mg，n = 24）的生物等效性研究数据，以及一项美沙拉嗪两次静脉注射（100mg和250mg，n = 6）的研究数据。总共进行了200次给药，获得并分析了血浆浓度 - 时间曲线。所有剂型的美沙拉嗪吸收存在很大差异。母体药物和美沙拉嗪乙酰化物的血浆浓度 - 时间曲线几乎平行，与剂型和剂量无关。采用经过验证的方法，通过库仑法或质谱检测的高效液相色谱分析测定血浆和尿液中美沙拉嗪及美沙拉嗪乙酰化物的浓度。
由于美沙拉嗪在药物制剂和给药过程中的释放和吸收存在很大差异，有可能证明乙酰化发生在肠壁和肝脏。通过将口服和直肠给药数据与静脉给药数据进行比较，可以指出在肠壁、肝脏或两者中乙酰化发生的位置（以及程度）。直肠给予美沙拉嗪栓剂和静脉给药会导致肝脏乙酰化。口服美沙拉嗪会导致肠壁和肝脏均发生乙酰化。对于耐胃酸片剂，肠壁乙酰化量占剂量的30%，对于缓释片则占剂量的40%。
