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Kvitne, K. E.Univ Oslo, Dept Pharm, Sect Pharmacol & Pharmaceut Biosci, POB 1068, N-0316 Oslo, Norway
(författare)
Correlations between 4 beta-hydroxycholesterol and hepatic and intestinal CYP3A4: protein expression, microsomal ex vivo activity, and in vivo activity in patients with a wide body weight range
- Artikel/kapitelEngelska2022
Förlag, utgivningsår, omfång ...
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2022-06-01
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Springer Science and Business Media LLC,2022
Nummerbeteckningar
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LIBRIS-ID:oai:gup.ub.gu.se/317055
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https://gup.ub.gu.se/publication/317055URI
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https://doi.org/10.1007/s00228-022-03336-9DOI
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-485602URI
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Purpose Variability in cytochrome P450 3A4 (CYP3A4) metabolism is mainly caused by non-genetic factors, hence providing a need for accurate phenotype biomarkers. Although 4 beta-hydroxycholesterol (4 beta OHC) is a promising endogenous CYP3A4 biomarker, additional investigations are required to evaluate its ability to predict CYP3A4 activity. This study investigated the correlations between 4 beta OHC concentrations and hepatic and intestinal CYP3A4 protein expression and ex vivo microsomal activity in paired liver and jejunum samples, as well as in vivo CYP3A4 phenotyping (midazolam) in patients with a wide body weight range. Methods The patients (n = 96; 78 with obesity and 18 normal or overweight individuals) were included from the COCKTAIL-study (NCT02386917). Plasma samples for analysis of 4 beta OHC and midazolam concentrations, and liver (n = 56) and jejunal (n = 38) biopsies were obtained. The biopsies for determination of CYP3A4 protein concentration and microsomal activity were obtained during gastric bypass or cholecystectomy. In vivo CYP3A4 phenotyping was performed using semi-simultaneous oral (1.5 mg) and intravenous (1.0 mg) midazolam. Results 4 beta OHC concentrations were positively correlated with hepatic microsomal CYP3A4 activity (rho = 0.53, p < 0.001), and hepatic CYP3A4 concentrations (rho = 0.30, p = 0.027), but not with intestinal CYP3A4 concentrations (rho = 0.18, p = 0.28) or intestinal microsomal CYP3A4 activity (rho = 0.15, p = 0.53). 4 beta OHC concentrations correlated weakly with midazolam absolute bioavailability (rho = - 0.23, p = 0.027) and apparent oral clearance (rho = 0.28, p = 0.008), but not with systemic clearance (rho = - 0.03, p = 0.81). Conclusion These findings suggest that 4 beta OHC concentrations reflect hepatic, but not intestinal, CYP3A4 activity. Further studies should investigate the potential value of 4 beta OHC as an endogenous biomarker for individual dose requirements of intravenously administered CYP3A4 substrate drugs.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Hole, K.Diakonhjemmet Hosp, Ctr Psychopharmacol, Oslo, Norway.;Oslo Metropolitan Univ, Dept Life Sci & Hlth, Oslo, Norway
(författare)
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Krogstad, V.Univ Oslo, Dept Pharm, Sect Pharmacol & Pharmaceut Biosci, POB 1068, N-0316 Oslo, Norway
(författare)
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Wollmann, B. M.Diakonhjemmet Hosp, Ctr Psychopharmacol, Oslo, Norway.
(författare)
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Wegler, ChristineUppsala universitet,Institutionen för farmaci,AstraZeneca, DMPK, Res & Early Dev Cardiovasc Renal & Metab CVRM, BioPharmaceut R&D, Gothenburg, Sweden(Swepub:uu)chrwe731
(författare)
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Johnson, L. K.Vestfold Hosp Trust, Morbid Obes Ctr, Tonsberg, Norway
(författare)
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Hertel, J. K.Vestfold Hosp Trust, Morbid Obes Ctr, Tonsberg, Norway
(författare)
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Artursson, PerUppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab(Swepub:uu)perartur
(författare)
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Karlsson, Cecilia,1968Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine,AstraZeneca, Clin Metab Cardiovasc Renal & Metab CVRM, Late Stage Dev, BioPharmaceut R&D, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden
(författare)
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Andersson, S.AstraZeneca, Oligonucleotide Discovery, Discovery Sci, R&D, Gothenburg, Sweden
(författare)
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Andersson, T. B.AstraZeneca, DMPK, Res & Early Dev Cardiovasc Renal & Metab CVRM, BioPharmaceut R&D, Gothenburg, Sweden
(författare)
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Sandbu, R.Vestfold Hosp Trust, Morbid Obes Ctr, Tonsberg, Norway.;Vestfold Hosp Trust, Dept Surg, T0nsberg, Norway
(författare)
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Hjelmesaeth, J.Vestfold Hosp Trust, Morbid Obes Ctr, Tonsberg, Norway.;Univ Oslo, Dept Endocrinol Morbid Obes & Prevent Med, Inst Clin Med, Oslo, Norway
(författare)
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Skovlund, E.Norwegian Univ Sci & Technol, Dept Publ Hlth & Nursing, NTNU, Trondheim, Norway
(författare)
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Christensen, H.Univ Oslo, Dept Pharm, Sect Pharmacol & Pharmaceut Biosci, POB 1068, N-0316 Oslo, Norway
(författare)
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Jansson-Lofmark, R.AstraZeneca, DMPK, Res & Early Dev Cardiovasc Renal & Metab CVRM, BioPharmaceut R&D, Gothenburg, Sweden
(författare)
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Asberg, A.Univ Oslo, Dept Pharm, Sect Pharmacol & Pharmaceut Biosci, POB 1068, N-0316 Oslo, Norway.;Oslo Univ Hosp, Dept Transplant Med, Oslo, Norway
(författare)
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Molden, E.Univ Oslo, Dept Pharm, Sect Pharmacol & Pharmaceut Biosci, POB 1068, N-0316 Oslo, Norway.;Diakonhjemmet Hosp, Ctr Psychopharmacol, Oslo, Norway
(författare)
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Robertsen, I.Univ Oslo, Dept Pharm, Sect Pharmacol & Pharmaceut Biosci, POB 1068, N-0316 Oslo, Norway
(författare)
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Univ Oslo, Dept Pharm, Sect Pharmacol & Pharmaceut Biosci, POB 1068, N-0316 Oslo, NorwayDiakonhjemmet Hosp, Ctr Psychopharmacol, Oslo, Norway.;Oslo Metropolitan Univ, Dept Life Sci & Hlth, Oslo, Norway
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:European Journal of Clinical Pharmacology: Springer Science and Business Media LLC78:8, s. 1289-12990031-69701432-1041
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Kvitne, K. E.
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Hole, K.
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Krogstad, V.
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Wollmann, B. M.
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Wegler, Christin ...
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Johnson, L. K.
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visa fler...
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Hertel, J. K.
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Artursson, Per
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Karlsson, Cecili ...
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Andersson, S.
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Andersson, T. B.
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Sandbu, R.
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Hjelmesaeth, J.
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Skovlund, E.
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Christensen, H.
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Jansson-Lofmark, ...
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Asberg, A.
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Molden, E.
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Robertsen, I.
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