Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway (V.K., I.R., A.Å., H.C.); Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway (V.K., A.Å.); Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Gothenburg, Sweden (A.P., C.W., S.A., T.B.A.); Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway (M.K.K.); Department of Health Sciences, OsloMet-Oslo Metropolitan University, Oslo, Norway (M.K.K.); Department of Pharmacy, Uppsala University, Uppsala, Sweden (C.W., P.A.); The Morbid Obesity Centre, Vestfold Hospital Trust, Tønsberg, Norway (P.C.A., J.H.); Department of Surgery, Vestfold Hospital Trust, Tønsberg, Norway (P.C.A.); Department of Endocrinology, Morbid Obesity and Preventive Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (J.H.); Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Gothenburg, Sweden (C.K.); Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (C.K.); and Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway (V.K., I.R., A.Å., H.C.); Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway (V.K., A.Å.); Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Gothenburg, Sweden (A.P., C.W., S.A., T.B.A.); Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway (M.K.K.); Department of Health Sciences, OsloMet-Oslo Metropolitan University, Oslo, Norway (M.K.K.); Department of Pharmacy, Uppsala University, Uppsala, Sweden (C.W., P.A.); The Morbid Obesity Centre, Vestfold Hospital Trust, Tønsberg, Norway (P.C.A., J.H.); Department of Surgery, Vestfold Hospital Trust, Tønsberg, Norway (P.C.A.); Department of Endocrinology, Morbid Obesity and Preventive Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (J.H.); Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Gothenburg, Sweden (C.K.); Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (C.K.); and Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden (T.B.A.).
Drug Metab Dispos. 2020 Jan;48(1):8-17. doi: 10.1124/dmd.119.087940. Epub 2019 Nov 4.
The liver and small intestine restrict oral bioavailability of drugs and constitute the main sites of pharmacokinetic drug-drug interactions. Hence, detailed data on hepatic and intestinal activities of drug metabolizing enzymes is important for modeling drug disposition and optimizing pharmacotherapy in different patient populations. The aim of this study was to determine the activities of seven cytochrome P450 (P450) enzymes in paired liver and small intestinal samples from patients with obesity. Biopsies were obtained from 20 patients who underwent Roux-en-Y gastric bypass surgery following a 3-week low-energy diet. Individual hepatic and intestinal microsomes were prepared and specific probe substrates in combined incubations were used for determination of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A activities. The activities of CYP2C8, CYP2C9, CYP2D6, and CYP3A were quantified in both human liver microsomes (HLM) and human intestinal microsomes (HIM), while the activities of CYP1A2, CYP2B6, and CYP2C19 were only quantifiable in HLM. Considerable interindividual variability was present in both HLM (9- to 23-fold) and HIM (5- to 55-fold). The median metabolic HLM/HIM ratios varied from 1.5 for CYP3A to 252 for CYP2C8. The activities of CYP2C9 in paired HLM and HIM were positively correlated ( = 0.74, < 0.001), while no interorgan correlations were found for activities of CYP2C8, CYP2D6, and CYP3A ( > 0.05). Small intestinal CYP3A activities were higher in females compared with males ( < 0.05). Hepatic CYP2B6 activity correlated negatively with body mass index ( = -0.72, < 0.001). These data may be useful for further in vitro-in vivo predictions of drug disposition in patients with obesity. SIGNIFICANCE STATEMENT: Hepatic and intestinal drug metabolism is the key determinant of oral drug bioavailability. In this study, paired liver and jejunum samples were obtained from 20 patients with obesity undergoing gastric bypass surgery following a 3-week low-energy diet. We determined the hepatic and small intestinal activities of clinically important P450 enzymes and provide detailed enzyme kinetic data relevant for predicting in vivo disposition of P450 substrates in this patient population.
肝脏和小肠限制了药物的口服生物利用度，并构成了药代动力学药物相互作用的主要部位。因此，详细了解药物代谢酶在肝和肠中的活性对于在不同患者人群中模拟药物处置和优化药物治疗非常重要。本研究的目的是确定 20 例肥胖患者肝和小肠组织中 7 种细胞色素 P450（CYP）酶的活性。这些患者在接受 3 周低能量饮食后，接受 Roux-en-Y 胃旁路手术。从每个患者中获得肝和空肠活检组织，在联合孵育中使用特定的探针底物来确定 CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6 和 CYP3A 的活性。CYP2C8、CYP2C9、CYP2D6 和 CYP3A 的活性在人肝微粒体（HLM）和人肠微粒体（HIM）中都进行了定量分析，而 CYP1A2、CYP2B6 和 CYP2C19 的活性仅能在 HLM 中定量分析。HLM（9-23 倍）和 HIM（5-55 倍）之间存在显著的个体间变异性。代谢的 HLM/HIM 比值中位数从 CYP3A 的 1.5 到 CYP2C8 的 252 不等。配对的 HLM 和 HIM 中 CYP2C9 的活性呈正相关（=0.74，<0.001），而 CYP2C8、CYP2D6 和 CYP3A 的活性之间没有器官间相关性（>0.05）。与男性相比，女性的小肠 CYP3A 活性更高（<0.05）。肝 CYP2B6 活性与体重指数呈负相关（=−0.72，<0.001）。这些数据可能有助于进一步对肥胖患者药物处置的体外-体内预测。
肝和肠道药物代谢是口服药物生物利用度的关键决定因素。在这项研究中，从 20 例接受胃旁路手术的肥胖患者中获得了肝和空肠组织样本，这些患者在接受 3 周低能量饮食后进行了手术。我们测定了临床重要的 CYP 酶在肝和小肠中的活性，并提供了与预测该患者群体中 CYP 底物体内处置相关的详细酶动力学数据。
