Activation of the peroxisome proliferator-activated receptor α (PPARα) is associated with increased fatty acid catabolism and is commonly targeted for the treatment of hyperlipidemia. To identify latent, endogenous biomarkers of PPARα activation and hence increased fatty acid β-oxidation, healthy human volunteers were given fenofibrate orally for 2 weeks and their urine profiled by UPLC-QTOFMS. Biomarkers identified by the machine learning algorithm random forests included significant depletion by day 14 of both pantothenic acid (>5-fold) and acetylcarnitine (>20-fold), observations that are consistent with known targets of PPARα including pantothenate kinase and genes encoding proteins involved in the transport and synthesis of acylcarnitines. It was also concluded that serum cholesterol (-12.7%), triglycerides (-25.6%), uric acid (-34.7%), together with urinary propylcarnitine (>10-fold), isobutyrylcarnitine (>2.5-fold), (S)-(+)-2-methylbutyrylcarnitine (5-fold), and isovalerylcarnitine (>5-fold) were all reduced by day 14. Specificity of these biomarkers as indicators of PPARα activation was demonstrated using the Ppara-null mouse. Urinary pantothenic acid and acylcarnitines may prove useful indicators of PPARα-induced fatty acid β-oxidation in humans. This study illustrates the utility of a pharmacometabolomic approach to understand drug effects on lipid metabolism in both human populations and in inbred mouse models.

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Abstract:Objectives: The aim of our study was to evaluate impact of CYP2D6 and MDR1 polymorphisms on the analgesic effi cacy of tramadol in patients after a knee arthroscopy. Background : Pharmacokinetics of tramadol and its metabolites is stereoselective and displays high interindividual variability correlating with polymorphic CYP2D6 in the population. Available data provide controversial results regarding the analgesic effi cacy of tramadol in subjects with different CYP2D6 genotypes. Methods: Pain intensity was assessed using visual analogue scale at 2 and 24 hours after the knee arthroscopy in 156 patients. Polymorphisms CYP2D6*3,*4,*5,*6, and gene duplication and C3435T in MDR1 gene were analyzed by PCR -RFLP. Results: Mean VAS 2h value in the whole study group was 44.0 ± 16.5 mm. Mean pain difference, was lowest in the UM group and highest in the PM group. The pain difference varied signifi cantly among the CYP2D6 subgroups (F = 4.29; p = 0.006) with signifi cant differences between homEM vs hetEM, homEM vs PM, and UM vs PM subgroups. There were no signifi cant differences among MDR1 subgroups with regards of pain difference. Mean tramadol consumption was 2.47 ± 1.17 mg/kg during the 24 h period. There were no signifi cant differences in the drug consumption, reporting of adverse reactions, need for rescue analgesic medication or verbal description of pain among the CYP2D6 or MDR1 genotype subgroups. Conclusion: CYP2D6 plays a signifi cant role in tramadol analgesic effi cacy. The non-opioid analgesia in PMs was associated with better subjective pain relief in patients after a knee arthroscopy (Tab. 3, Ref. 18). Full Text in PDF www.elis.sk.