Effects Of Aerobic Exercise On Pharmacokinetics Of A Cyp450 Probe Drug Cocktail

Aerobic exercise is associated with inflammatory responses similar to pro-inflammatory stimuli previously shown to decrease CYP450 drug metabolizing enzyme (DME) activities, like infection and metabolic diseases. However, it is unknown whether the inflammatory response to exercise similarly impacts DME activity. PURPOSE: To determine if aerobic exercise and its resulting inflammatory response elicit changes in DME activities as determined by changes in the pharmacokinetics (PK) of a cocktail of 5 drugs ingested simultaneously as micro-/milli-doses in a cocktail. METHODS: In a cross-over study design, 10 male participants underwent two trials assigned in a random order. Each trial started with either a day of sedentarism (Rest) or 1 h of treadmill running at 65 or 75% V̇O2max (EXS), and were followed by two days during which participants ingested micro-/milli-doses (i.e., 100 μg to 10 mg) of five drugs (caffeine, losartan, omeprazole, dextromethorphan, & midazolam) that are each metabolized primarily by a specific CYP450 enzyme and, thus, served as a probe for CYP1A2, 2C9, 2C19, 2D6, & 3A4, respectively. Venous blood samples obtained over the 48 h post-dosing period were assayed for drug, metabolite, and cytokine concentrations. Drug and metabolite concentrations were used to construct metabolic ratios (MRs) and compartmental PK models that were fitted using Monolix, and genotypes of participant DMEs were determined via cheek swab samples. RESULTS: EXS significantly increased the plasma concentrations of the cytokines IL-6 (5.62 ± 4.87 vs. 1.88 ± 0.96 pg/mL, p < .005), IL-8 (5.64 ± 3.59 vs. 3.25 ± 1.45 pg/mL, p < .05), and IL-10 (0.77 ± 0.53 vs. 0.33 ± 0.15 pg/mL, p < .001), but not TNF-α or IFN-γ. Compartmental PK models were constructed for each set of drug data. There were no inter-trial differences in the PK parameters or MRs of the probe drug cocktail, but the model-predicted oral clearance (dose/AUCpo) of omeprazole was consistent with 2C19 genotypes (βCLpm-2C19*extensive metabolizers = 0.71, p < .001; βCLpm-2C19*ultrarapid metabolizers = 0.77, p < .001) and correlated with participant fitness (V̇O2max; r = 0.76, p < .001). CONCLUSIONS: One hour of moderate intensity aerobic exercise that elicits a mild inflammatory response is unlikely to affect the clearance of most orally ingested drugs.