Altered Diurnal Rhythm of Intestinal Peptide Transporter by Fasting and Its Effects on the Pharmacokinetics of Ceftibuten

Abstract

We previously demonstrated that Hϩ /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 C max 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.

Bile Acid-regulated Peroxisome Proliferator-activated Receptor-α (PPARα) Activity Underlies Circadian Expression of Intestinal Peptide Absorption Transporter PepT1/Slc15a1

“…Previous studies using PPAR␣-null mice demonstrated that Slc15a1 is typical of PPAR␣ target genes whose expression oscillates in a circadian time-dependent as well as feeding state-dependent manner (28). Although a molecular component of circadian clock has been shown to govern the daily expression of Slc15a1 in laboratory rats (12), the present study demonstrated that the suppressing action of bile acids on PPAR␣ activity is involved in the circadian regulation of the expression of Slc15a1 in mouse intestinal epithelial cells.…”

Clock is important for food and circadian regulation of macronutrient absorption in mice

“…Several theories, including lumenal signals, vagal communications, and humoral regulations, have been proposed to explain diurnal regulation of intestinal transporters ( 5 ). Previously, we showed that diurnal regulation of the SGLT1 and PEPT1 mRNA is maintained in rats food-deprived for 4 days ( 33 ). Here, we observed that several nutrient transport proteins do not show circadian expressions in Clk mt/mt mice.…”

“…Several studies indicate that transporters involved in the absorption of fat, carbohydrates, and proteins show diurnal rhythms. For example, apical Na + /glucose cotransporter 1 (SGLT1) and fructose transporter 5 (GLUT5) as well as the basolateral hexose transporter GLUT2 show rhythmic expression (31)(32)(33)(34)(35)(36). In addition, the expression of protoncoupled, oligopeptide transporter 1 (PEPT1), which is also a nutrient and drug transporter, shows diurnal expression ( 32,37 ).…”

The skeletal muscle circadian clock: current insights

“…The absorption and metabolism of dietary protein in other organs might cause time-dependent acceleration of protein synthesis in skeletal muscle, because the activity and expression of the intestinal H + peptide cotransporter PEPT1 is diurnally regulated. 79,80 Lipton et al indicated that hepatic BMAL1 is rhythmically phosphorylated by the mTOR-effector kinase S6K1 and associated with translational machinery, suggesting that BMAL1 regulates the oscillation of protein synthesis independently of its role in transcriptional regulation. 58 Further study is required to elucidate whether skeletal muscle protein synthesis oscillates in a circadian manner and whether it is relevant to muscle clock function.…”