Abstract
To characterize effects of type 2 diabetes (T2D) on mRNA expression levels for 10 Cytochromes P450 (CYP450s), two carboxylesterases, and three drug transporters (ABCB1, ABCG2, SLCO2B1) in human duodenal biopsies. To compare drug metabolizing enzyme activities of four CYP450 isoenzymes in duodenal biopsies from patients with or without T2D. mRNA levels were quantified (RT-qPCR) in human duodenal biopsies obtained from patients with (n = 20) or without (n = 16) T2D undergoing a scheduled gastro-intestinal endoscopy. CYP450 activities were determined following incubation of biopsy homogenates with probe substrates for CYP2B6 (bupropion), CYP2C9 (tolbutamide), CYP2J2 (ebastine), and CYP3A4/5 (midazolam). Covariables related to inflammation, T2D, demographic, and genetics were investigated. T2D had no major effects on mRNA levels of all enzymes and transporters assessed. Formation rates of metabolites (pmoles mg protein−1 min−1) determined by LC-MS/MS for CYP2C9 (0.48 ± 0.26 vs. 0.41 ± 0.12), CYP2J2 (2.16 ± 1.70 vs. 1.69 ± 0.93), and CYP3A (5.25 ± 3.72 vs. 5.02 ± 4.76) were not different between biopsies obtained from individuals with or without T2D (p > 0.05). No CYP2B6 specific activity was measured. TNF-α levels were higher in T2D patients but did not correlate with any changes in mRNA expression levels for drug metabolizing enzymes or transporters in the duodenum. T2D did not modulate expression or activity of tested drug metabolizing enzymes and transporters in the human duodenum. Previously reported changes in drug oral clearances in patients with T2D could be due to a tissue-specific disease modulation occurring in the liver and/or in other parts of the intestines.
Highlights
Type 2 diabetes (T2D) is the most common form of diabetes mellitus worldwide and its global prevalence is increasing yearly [1]
To compare drug metabolizing enzyme activities of four Cytochrome P450s (CYP450s) isoenzymes in duodenal biopsies from patients with or without type 2 diabetes (T2D). mRNA levels were quantified (RT-qPCR) in human duodenal biopsies obtained from patients with (n = 20) or without (n = 16) T2D undergoing a scheduled gastro-intestinal endoscopy
In a clinical case-control pharmacokinetic study, our preliminary results showed that patients with T2D presented a decreased metabolic activity for CYP2B6, CYP2C19, and CYP3As following the oral administration of a cocktail of probe drugs [33,34]
Summary
Type 2 diabetes (T2D) is the most common form of diabetes mellitus worldwide and its global prevalence is increasing yearly [1]. Patients with T2D often require multiple drugs to treat their numerous comorbidities. They present a highly variable response to drugs: some T2D patients appear resistant to drugs while others are more sensitive (e.g., warfarin, clopidogrel, cyclosporine, tacrolimus, and anti-hypertensive agents) [2,3,4,5,6,7]. The exact mechanism underlying this interindividual variability in drug response is still unknown. Inter-subject variability in drug response is largely explained by drug pharmacokinetics and pharmacodynamics (PK-PD). First pass elimination of orally administered drugs involves both gastro-intestinal and hepatic-mediated metabolism and transport. In addition to the liver, the small intestine could be a major contributor to pre-systemic drug-metabolism and excretion (through efflux transporters)
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