Pan Xiaoyue, Terada Tomohiro, Okuda Masahiro, Inui Ken-ichi
Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan.
J Pharmacol Exp Ther. 2003 Nov;307(2):626-32. doi: 10.1124/jpet.103.055939. Epub 2003 Sep 11.
We previously demonstrated that H+/peptide cotransporter PEPT1 shows a diurnal rhythm in the rat small intestine. In the present study, we examined the effect of food intake on the diurnal rhythm of intestinal PEPT1 using fed and fasted rats and also determined whether such variation affected the pharmacokinetics of peptide-like drugs. In fed rats, PEPT1 protein level was significantly higher at 8:00 PM than at 8:00 AM. However, during fasting for 2 to 4 days, the differences of PEPT1 protein levels between 8:00 AM and 8:00 PM gradually disappeared. Intestinal absorption of an oral antibiotic ceftibuten (CETB), a pharmacological substrate for PEPT1, was also greater at 8:00 PM than at 8:00 AM in fed rats, but not different in 4-day fasted rats. In contrast to PEPT1 protein levels, PEPT1 mRNA levels retained a diurnal rhythm after 4 days of fasting. Pharmacokinetic analyses of CETB after intraintestinal administration demonstrated that both Cmax and area under the plasma concentration-time curve from 0 to 3 h were greater at 8:00 PM than at 8:00 AM in fed rats. In contrast, pharmacokinetic parameters showed no significant difference between 8:00 AM and 8:00 PM for intraintestinal administration in 4-day fasted rats and for intravenous administration in fed and 4-day fasted rats. These findings suggested that the diurnal rhythm of intestinal PEPT1 transport activity was disrupted by fasting and that diurnal variation of intestinal PEPT1 functionality could influence the pharmacokinetics of peptide-like drugs such as CETB.
我们之前证明，H⁺/肽共转运体PEPT1在大鼠小肠中呈现昼夜节律。在本研究中，我们使用喂食和禁食的大鼠研究了食物摄入对肠道PEPT1昼夜节律的影响，并确定这种变化是否会影响肽类药物的药代动力学。在喂食的大鼠中，PEPT1蛋白水平在晚上8点显著高于早上8点。然而，在禁食2至4天期间，早上8点和晚上8点之间PEPT1蛋白水平的差异逐渐消失。口服抗生素头孢布烯（CETB）是PEPT1的药理底物，在喂食的大鼠中，其肠道吸收在晚上8点也高于早上8点，但在禁食4天的大鼠中没有差异。与PEPT1蛋白水平相反，禁食4天后PEPT1 mRNA水平仍保持昼夜节律。肠道内给药后对CETB的药代动力学分析表明，在喂食的大鼠中，晚上8点的Cmax和0至3小时血浆浓度-时间曲线下面积均大于早上8点。相比之下，在禁食4天的大鼠中进行肠道内给药以及在喂食和禁食4天的大鼠中进行静脉内给药时，早上8点和晚上8点之间的药代动力学参数没有显著差异。这些发现表明，禁食会破坏肠道PEPT1转运活性的昼夜节律，并且肠道PEPT1功能的昼夜变化可能会影响CETB等肽类药物的药代动力学。
