Role of Peptide Transporter PEPT1 in the Intestinal Absorption and Pharmacokinetics of the Amino Acid Ester Prodrug Valacyclovir.

PEPT1;PEPT1-targeted Prodrugs;Valacyclovir;Intestinal Permeability;Pharmacy and Pharmacology;Health Sciences;Pharmaceutical Sciences

Yang, BeiSun, Duxin ;

University of Michigan

关键词: PEPT1;    PEPT1-targeted Prodrugs;    Valacyclovir;    Intestinal Permeability;    Pharmacy and Pharmacology;    Health Sciences;    Pharmaceutical Sciences;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/96119/beiyang_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Peptide transporter 1 (PEPT1), abundantly expressed in the small intestine, is a tempting delivery target for increasing the oral absorption of drugs and prodrugs which might otherwise have poor absorption. This dissertation project proposes to delineate the quantitative importance of PEPT1 in the intestinal absorption and pharmacokinetics of the model PEPT1-targeted prodrug valacyclovir.In wildtype and Pept1 knockout mice, the effective permeability of valacyclovir was evaluated as a function of perfusate pH, drug concentration, potential inhibitors and regional segments of the intestines using in situ perfusions. Results from the in situ studies showed that PEPT1 accounted for approximately 90% of valacyclovir permeability in mouse small intestine. Absorbed valacyclovir was completely converted to its active drug acyclovir in enterocytes. In wildtype mice, valacyclovir permeability was pH independent, concentration dependent, saturable with a Km of about 10 mM, and inhibited by known PEPT1 substrates. In vivo pharmacokinetic studies showed that PEPT1 had little impact on the pharmacokinetic profiles of acyclovir following its oral or intravenous dosing whereas PEPT1 deletion led to approximately 78% and 58% reductions in acyclovir maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC), respectively, after oral valacyclovir. Lastly, a mechanistic ACAT model, in which the primary input parameters were obtained from previous in situ and in vivo studies, reasonably simulated the intestinal absorption and pharmacokinetic profiles of valacyclovir after its oral administration in both genotypes. The duodenum (>40%) was the primary absorption site of valacyclovir in wildtype mice while the more distal jejunal (~13%) and ileal (~10%) segments played a more important role in valacyclovir absorption for Pept1 knockout animals. Rapid luminal hydrolysis was the main cause of incomplete valacyclovir absorption in wildtype mice.In conclusion, results from this dissertation provided convincing evidence to validate the major contribution of PEPT1 on the intestinal absorption of valacyclovir and, furthermore, the utilization of PEPT1 as an oral delivery target. In silico mechanistic modeling aided in the interpretation of in situ and in vivo experimental results, and could be a useful tool in facilitating our understanding of valacyclovir’s complicated intestinal absorption processes.