Drug Disposition Protein Quantification in Matched Human Jejunum and Liver From Donors With Obesity

Wegler, Christine; Wiśniewski, Jacek R.; Robertsen, Ida; Christensen, Hege; Hertel, Jens Kristoffer; Hjelmesæth, Jøran; Jansson‐Löfmark, Rasmus; Åsberg, Anders; Andersson, Tommy; Artursson, Per

doi:10.1002/cpt.2558

Cited by 31 publications

(35 citation statements)

References 62 publications

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“…The protein quantification has been described previously. 30 In brief, proteins were extracted from liver and jejunal biopsies in a sodium dodecyl sulfate (SDS)containing (2% w/v) lysis buffer, and processed with the multi-enzyme digestion filter-aided sample preparation protocol, using LysC and trypsin. Proteomics analysis was performed with Q Exactive HF or Q Exactive HF-X.…”

Section: Protein Quantification Of Cyp Enzymes In Liver and Jejunal B...mentioning

confidence: 99%

Impact of type 2 diabetes on in vivo activities and protein expressions of cytochrome P450 in patients with obesity

Kvitne

Åsberg

Johnson

et al. 2022

Clinical Translational Sci

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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 (T2DMobesity), 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/μg 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. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?The current literature suggests that type 2 diabetes mellitus (T2DM) alters cytochrome P450 (CYP) activities in an iso-specific manner. However, an important limitation of previous studies investigating the impact of T2DM on CYP activities is that the close link between T2DM and obesity has not have been accounted for.

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Section: Protein Quantification Of Cyp Enzymes In Liver and Jejunal B...mentioning

confidence: 99%

Impact of type 2 diabetes on in vivo activities and protein expressions of cytochrome P450 in patients with obesity

Kvitne

Åsberg

Johnson

et al. 2022

Clinical Translational Sci

Self Cite

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“…The estimated thiamine portal vein concentration of ~ 0.5 μM is close to saturating ThTR‐2 and suggests that both OCT1 and ThTR‐2 could play a role in hepatic uptake of thiamine. OCT1 expression levels in the liver are much higher than ThTR‐2 levels, 41 consistent with it being a higher capacity thiamine transporter; thus, OCT1 may increasingly play a more predominant role in hepatic thiamine uptake at increasing oral thiamine doses. Our results are not consistent with the results of a study investigating the disposition of a high dose (200 mg) of thiamine in individuals with reduced function OCT1 polymorphisms, which showed no effect of the polymorphisms on thiamine disposition at this dose 40 .…”

Section: Discussionmentioning

confidence: 83%

The Effect of Trimethoprim on Thiamine Absorption: A Transporter‐Mediated Drug‐Nutrient Interaction

Vora

Wen

Yee

et al. 2023

Clin Pharma and Therapeutics

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Trimethoprim is predicted to inhibit several thiamine transporters, including the primary thiamine intestinal absorptive transporter, ThTR‐2, and the hepatic and renal organic cation transporters, OCT1, OCT2, and MATEs. To investigate the effect of trimethoprim on thiamine absorption, studies were conducted in cells, mice, and healthy volunteers and supported by use of real‐world data. In a randomized, crossover clinical study, seven healthy volunteers were given a single oral dose of thiamine or thiamine plus trimethoprim, followed by blood sampling. The thiamine area under the curve (AUC) increased with trimethoprim co‐administration (P value = 0.031). Similar results were seen in mice. Trimethoprim appeared to act on thiamine absorption through inhibition of hepatic OCT1 as evidenced from its ability to modulate levels of isobutyrylcarnitine and propionylcarnitine, OCT1 biomarkers identified from metabolomic analyses. Real‐world data further supported this finding, showing an association between trimethoprim use and higher levels of triglycerides, LDL cholesterol, and total cholesterol, consistent with OCT1 inhibition (P values: 2.2 × 10−16, 5.75 × 10−7, and 5.82 × 10−7, respectively). These findings suggest that trimethoprim increases plasma levels of thiamine by inhibiting hepatic OCT1. Trimethoprim reduced urinary excretion and clearance of biomarkers for OCT2 and MATEs, consistent with inhibition of renal organic cation transporters. This inhibition did not appear to play a role in the observed increases in thiamine levels. This study highlights the potential for drug‐nutrient interactions involving transporters, in addition to transporters' established role in drug–drug interactions.

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“…Wegler et al reported the protein levels of drug-metabolizing enzymes and transporters in the jejunum using a large sample size. 53 Direct comparison of our data with theirs is difficult because the MSbased DIA untargeted proteomics used in our study are generally considered not applicable for comparisons of expression levels among different proteins. However, the present results together with the report of Wegler et al would be useful for elucidating interindividual and regional differences in the expressions of pharmacokinetics-related proteins in the human intestine.…”

Section: ■ Discussionmentioning

confidence: 99%

“…One of the limitations in this study is that the sample sizes were relatively small (61 biopsy samples, 61 samples for RNA-seq, and 27 samples for LC–MS/MS); the numbers of biopsies of the jejunum and rectum were particularly at 3 each. Wegler et al reported the protein levels of drug-metabolizing enzymes and transporters in the jejunum using a large sample size . Direct comparison of our data with theirs is difficult because the MS-based DIA untargeted proteomics used in our study are generally considered not applicable for comparisons of expression levels among different proteins.…”

Section: Discussionmentioning

confidence: 99%

Regional Transcriptomics and Proteomics of Pharmacokinetics-Related Genes in Human Intestine

et al. 2023

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The intestine is an organ responsible for the absorption and metabolism of orally administered drugs. To predict pharmacokinetics behavior in the small intestine, it is necessary to examine the human intestinal expression profiles of the genes related to drug absorption, distribution, metabolism, and excretion (ADME). In this study, to obtain more accurate expression profiles in various regions of the human intestine, biopsy samples were collected from endoscopically noninflamed mucosa of the duodenum, jejunum, ileum, colon, and rectum from Japanese including Crohn's disease or ulcerative colitis patients, and both RNA-seq and quantitative proteomics analyses were performed. We also analyzed the expression of drug-metabolizing enzymes (cytochromes P450 (CYPs) and non-CYP enzymes), drug transporters, and nuclear receptors. Overall, the mRNA expression levels of these ADME-related genes correlated highly with the protein expression levels. The characteristics of the expression of ADME-related genes differed significantly between the small and large intestines, including the expression levels of CYP enzymes, which were higher and lower in the small and large intestines, respectively. Most CYPs were expressed dominantly in the small intestine, especially the jejunum, but were rarely expressed in the large intestine. On the other hand, non-CYP enzymes were expressed in the large intestine but at lower expression levels than in the small intestine. Moreover, the expression levels of drug metabolizing enzyme genes differed even between the proximal and distal small intestine. Transporters were expressed most highly in the ileum. The data in the present study will enhance understanding of the intestinal ADME of drug candidates and would be useful for drug discovery research.

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Drug Disposition Protein Quantification in Matched Human Jejunum and Liver From Donors With Obesity

Cited by 31 publications

References 62 publications

Impact of type 2 diabetes on in vivo activities and protein expressions of cytochrome P450 in patients with obesity

Impact of type 2 diabetes on in vivo activities and protein expressions of cytochrome P450 in patients with obesity

The Effect of Trimethoprim on Thiamine Absorption: A Transporter‐Mediated Drug‐Nutrient Interaction

Regional Transcriptomics and Proteomics of Pharmacokinetics-Related Genes in Human Intestine

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