Abstract

Purpose: The effect of Roux-en-Y gastric bypass (RYGB) on the bioavailability of orally administered drugs is unknown. Cytochrome P450 3A (CYP3A) is the major human drug metabolizing enzyme and it metabolizes many important compounds (e.g., macrolides, tacrolimus, diltiazem). CYP3A enzyme is present in both small intestine and liver. We conducted a study to systematically examine the effect of RYGB on CYP3A in humans. Methods: Sixteen subjects who were at least one year post RYGB and 16 age, race, gender and BMI-matched healthy volunteers without RYGB participated in this study. CYP3A activity was measured using oral and IV midazolam as in vivo probe drugs. Participants received midazolam 1mg orally followed by midazolam 0.01ml/kg intravenously 6 hours later and timed peripheral venous blood sampling was performed per protocol. CYP3A enzyme activity was estimated using the plasma ratios of area under the serum concentration-time curves (AUC 0-t) of oral midazolam and its primary metabolite, 1 ‘OH midazolam. Absorption pharmacokinetics (Cmax, Tmax, and AUC) were also compared between the two groups. Results: There were no statistically significant differences in the demographics between the two groups (Table 1). Difference in ratios of AUC 0-6 values of oral midazolam and 1 ‘OH midazolam between the RYGB and control groups were not statistically significant (5.5±1.1 uM vs. 33.4±24.7 uM, p=0.26). Compared to controls, patients with RYGB did not have significantly different Cmax (2.33±0.48 ng/mL vs. 6.44±2.85 ng/mL, p=0.19) or AUC 0-6 (3.88±0.68 ng*hr*mL-1 vs. 14.07±5.98 ng*hr*mL-1, p=0.11), but their Tmax significantly shorter (0.53±0.05 vs. 0.82±0.09 hrs, p=0.04). There were no statistically significant differences in the Cmax, Tmax, AUC or hepatic CYP3A activity following IV midazolam (Table 1).Table 1: Demographics and Pharmacokinetic data on RYGB and age, race, gender, BMI-matched controlsConclusion: Shorter Tmax of oral midazolam in patients with RYGB suggests that they absorb oral CYP3A substrates more rapidly than controls, but similar Cmax and AUC values between two groups indicate that absorption kinetics of oral CYP3A substrates are not significantly affected by RYGB. Small bowel and liver CYP3Aactivity in patients with RYGB is not different when compared to controls. Our results suggest that patients with RYGB do not need dosage adjustment of orally administered CYP3A substrates.

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