PMID- 36037309 OWN - NLM STAT- MEDLINE DCOM- 20221121 LR - 20230125 IS - 1752-8062 (Electronic) IS - 1752-8054 (Print) IS - 1752-8054 (Linking) VI - 15 IP - 11 DP - 2022 Nov TI - Impact of type 2 diabetes on in vivo activities and protein expressions of cytochrome P450 in patients with obesity. PG - 2685-2696 LID - 10.1111/cts.13394 [doi] AB - Previous studies have not accounted for the close link between type 2 diabetes mellitus (T2DM) and obesity when investigating the impact of T2DM on cytochrome P450 (CYP) activities. The aim was to investigate the effect of T2DM on in vivo activities and protein expressions of CYP2C19, CYP3A, CYP1A2, and CYP2C9 in patients with obesity. A total of 99 patients from the COCKTAIL study (NCT02386917) were included in this cross-sectional analysis; 29 with T2DM and obesity (T2DM-obesity), 53 with obesity without T2DM (obesity), and 17 controls without T2DM and obesity (controls). CYP activities were assessed after the administration of a cocktail of probe drugs including omeprazole (CYP2C19), midazolam (CYP3A), caffeine (CYP1A2), and losartan (CYP2C9). Jejunal and liver biopsies were also obtained to determine protein concentrations of the respective CYPs. CYP2C19 activity and jejunal CYP2C19 concentration were 63% (-0.39 [95% CI: -0.82, -0.09]) and 40% (-0.09 fmol/mug protein [95% CI: -0.18, -0.003]) lower in T2DM-obesity compared with the obesity group, respectively. By contrast, there were no differences in the in vivo activities and protein concentrations of CYP3A, CYP1A2, and CYP2C9. Multivariable regression analyses also indicated that T2DM was associated with interindividual variability in CYP2C19 activity, but not CYP3A, CYP1A2, and CYP2C9 activities. The findings indicate that T2DM has a significant downregulating impact on CYP2C19 activity, but not on CYP3A, CYP1A2, and CYP2C9 activities and protein concentrations in patients with obesity. Hence, the effect of T2DM seems to be isoform-specific. CI - (c) 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. FAU - Kvitne, Kine Eide AU - Kvitne KE AUID- ORCID: 0000-0001-8118-7660 AD - Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway. FAU - Asberg, Anders AU - Asberg A AUID- ORCID: 0000-0002-0628-1769 AD - Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway. AD - Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway. FAU - Johnson, Line K AU - Johnson LK AD - The Morbid Obesity Center, Vestfold Hospital Trust, Tonsberg, Norway. FAU - Wegler, Christine AU - Wegler C AD - Department of Pharmacy, Uppsala University, Uppsala, Sweden. AD - DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. FAU - Hertel, Jens K AU - Hertel JK AD - The Morbid Obesity Center, Vestfold Hospital Trust, Tonsberg, Norway. FAU - Artursson, Per AU - Artursson P AUID- ORCID: 0000-0002-3708-7395 AD - Department of Pharmacy and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. FAU - Karlsson, Cecilia AU - Karlsson C AUID- ORCID: 0000-0002-4299-8775 AD - Late-stage Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. AD - Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. FAU - Andersson, Shalini AU - Andersson S AD - Oligonucleotide Discovery, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden. FAU - Sandbu, Rune AU - Sandbu R AD - The Morbid Obesity Center, Vestfold Hospital Trust, Tonsberg, Norway. AD - Department of Surgery, Vestfold Hospital Trust, Tonsberg, Norway. FAU - Skovlund, Eva AU - Skovlund E AD - Department of Public Health and Nursing, Norwegian University of Science and Technology, NTNU, Trondheim, Norway. FAU - Christensen, Hege AU - Christensen H AD - Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway. FAU - Jansson-Lofmark, Rasmus AU - Jansson-Lofmark R AD - DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. FAU - Hjelmesaeth, Joran AU - Hjelmesaeth J AD - The Morbid Obesity Center, Vestfold Hospital Trust, Tonsberg, Norway. AD - Department of Endocrinology, Morbid Obesity and Preventive Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. FAU - Robertsen, Ida AU - Robertsen I AD - Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway. LA - eng SI - ClinicalTrials.gov/NCT02386917 PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220908 PL - United States TA - Clin Transl Sci JT - Clinical and translational science JID - 101474067 RN - EC 1.14.14.1 (Cytochrome P-450 CYP1A2) RN - EC 1.14.14.1 (Cytochrome P-450 CYP2C19) RN - EC 1.14.13.- (Cytochrome P-450 CYP2C9) RN - EC 1.14.14.1 (Cytochrome P-450 CYP3A) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) SB - IM MH - Humans MH - Cross-Sectional Studies MH - *Cytochrome P-450 CYP1A2/metabolism MH - Cytochrome P-450 CYP2C19/genetics/metabolism MH - Cytochrome P-450 CYP2C9/metabolism MH - Cytochrome P-450 CYP3A/metabolism MH - Cytochrome P-450 Enzyme System/metabolism MH - *Diabetes Mellitus, Type 2 MH - Drug Interactions MH - Obesity MH - Clinical Studies as Topic PMC - PMC9652437 COIS- C.K., S.A., and R.J.-L. are AstraZeneca employees and own shares in AstraZeneca, while C.W. is a former AstraZeneca employee. All other authors declared no competing interests for this work. EDAT- 2022/08/30 06:00 MHDA- 2022/11/16 06:00 PMCR- 2022/11/01 CRDT- 2022/08/29 14:52 PHST- 2022/08/18 00:00 [revised] PHST- 2022/05/30 00:00 [received] PHST- 2022/08/18 00:00 [accepted] PHST- 2022/08/30 06:00 [pubmed] PHST- 2022/11/16 06:00 [medline] PHST- 2022/08/29 14:52 [entrez] PHST- 2022/11/01 00:00 [pmc-release] AID - CTS13394 [pii] AID - 10.1111/cts.13394 [doi] PST - ppublish SO - Clin Transl Sci. 2022 Nov;15(11):2685-2696. doi: 10.1111/cts.13394. Epub 2022 Sep 8.