This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The objective of this research study is to characterize and explain the influence of Roux-en-Y gastric bypass surgery (RYGB) on the absorption and metabolism of drugs and nutrients. Specifically, the design is aimed to compare and quantify the absorptive and metabolic functions of the small intestine before and after RYGB, and determine the characteristics and mechanism that may explain the changes. Currently, no information is available in the literature addressing these issues. This pilot study will enroll up to 12 patients who undergo RYGB as medically indicated. The study will assess the impact of RYGB on gastric emptying and substrate absorption by comparing the pharmacokinetics of oral acetaminophen (an established marker to determine gastric emptying) before, 3, and 12 months after RYGB. The presystemic effect of the intestine will be quantitatively assessed by the pharmacokinetics of orally administered midazolam and digoxin (markers to assess the activities of the major intestinal drug metabolizing enzyme (CYP3A4) and transporter (P-glycoprotein), respectively). Serial blood draws will be performed to determine the pharmacokinetics of these marker drugs, which will be compared before and after RYGB. In addition, intestinal tissue samples will be obtained from the surgery and through an endoscopic biopsy 12 months after RYGB to assess and compare the expressions of the CYP3A4 and P-gp genes using real-time polymerase chain reaction. Impact: This proposal is intended to be a pilot project that would lead to a series of in-depth investigations to further understand the mechanism behind the successful weight loss after RYGB.
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