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A reliable translation of in vitro and preclinical data on drug absorption, distribution, metabolism, and excretion (ADME) to humans is important for safe and effective drug development. Precision medicine that is expected to provide the right clinical dose for the right patient at the right time requires a comprehensive understanding of population factors affecting drug disposition and response. Characterization of drug-metabolizing enzymes and transporters for the protein abundance and their interindividual as well as differential tissue

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Interventions to decrease inflammation and improve metabolic function hold promise for the prevention of obesity-related diseases. Methylsulfonylmethane (MSM) is a naturally occurring compound that demonstrates antioxidant and anti-inflammatory effects. Improvements in measures of metabolic health have been observed in mouse models of obesity and diabetes following MSM treatment. However, the effects of MSM on obesity-related diseases in humans have not been investigated. Therefore, the purpose of this investigation was to determine whether MSM supplementation improves cardiometabolic health, and markers of inflammation and oxidative status. A randomized, double-blind, placebo-controlled design was utilized with a total of 22 overweight or obese adults completing the study. Participants received either a placebo (white rice flour) or 3 g MSM daily for 16 weeks. Measurements occurred at baseline and after 4, 8, and 16 weeks. Outcome measures included fasting glucose, insulin, blood lipids, blood pressure, body composition, metabolic rate, and markers of inflammation and oxidative status. The primary finding of this work shows that high-density lipoprotein cholesterol was elevated at 8 and 16 weeks of daily MSM consumption compared to baseline, (p = 0.008, p = 0.013). Our findings indicate that MSM supplementation may improve the cholesterol profile by resulting in higher levels of high-density lipoprotein cholesterol.

Testosterone exhibits high variability in pharmacokinetics and glucuronidation after oral administration. While testosterone metabolism has been studied for decades, the impact of UGT2B17 gene deletion and the role of gut bacterial β-glucuronidases on its disposition are not well characterized. We first performed an exploratory study to investigate the effect of UGT2B17 gene deletion on the global liver proteome, which revealed significant increases in proteins from multiple biological pathways. The most upregulated liver proteins were aldoketoreductases (AKR1D1, AKR1C4, AKR7A3, AKR1A1, 7-dehydrocholesterol reductase (DHCR7)) and alcohol or aldehyde dehydrogenases (ADH6, ADH1C, ALDH1A1, ALDH9A1, and ALDH5A). In vitro assays revealed that AKR1D1 and AKR1C4 inactivate testosterone to 5β-dihydrotestosterone (5β-DHT) and 3α, 5β-tetrahydrotestosterone (3α, 5β-THT), respectively. These metabolites also appeared in human hepatocytes treated with testosterone and in human serum collected after oral testosterone dosing in men. Second, we evaluated the fate of testosterone glucuronide (TG) secreted into the intestinal lumen and its potential reactivation into testosterone. Incubation of TG with purified gut microbial β-glucuronidase (GUS) enzymes and with human fecal extracts confirmed testosterone reactivation by gut bacterial enzymes. Our exploratory study suggests that testosterone is metabolized by AKRs to 5β-DHT and 3α, 5β-THT in individuals harboring a UGT2B17 deletion, and these metabolites are then eliminated through glucuronidation by another UGT isoforms, UGT2B7. Both testosterone metabolic switching and variable testosterone activation by gut microbial enzymes are important mechanisms for explaining disposition of orally administered testosterone, and appear essential to unraveling the molecular mechanisms underlying UGT2B17-associated pathophysiological conditions.