Pharmacokinetic variability in patients with obesity and healthy individuals – the role of cytochrome P450

Abstract

Disease-related factors have proven to be an important source of variable drug response among individuals, leading to an increased focus on the impact of various diseases on pharmacokinetics. Due to the rising prevalence of obesity and its comorbidities, and hence the number of bariatric surgeries, clinicians will more often be confronted with how drugs should be dosed in these patients. The overall aim of this thesis was to investigate the impact of obesity, Roux-en-Y gastric bypass (RYGB), weight loss, and type 2 diabetes mellitus (T2DM) on pharmacokinetics, focusing on cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, and CYP3A. This thesis is primarily based on data from the COCKTAIL-study including patients with obesity scheduled for weight loss treatment with RYGB or a strict diet and a non-obese control group scheduled for cholecystectomy. In two of the papers, we showed that metabolism mediated by CYPC219 and CYP3A were decreased in patients with obesity, and, following weight loss induced by RYGB or a strict diet, CYP2C19 activity increased a few weeks later, while CYP3A activity had a longer recovery time. We also showed that body weight, weight loss, and RYGB had a negligible impact on CYP1A2 and CYP2C9 activities. This thesis also included a paper investigating the impact of T2DM in patients with obesity with or without T2DM, where we showed that T2DM downregulated CYP2C19 activity beyond that of obesity, while CYP1A2, CYP2C9, and CYP3A were not influenced. In the data from the COCKTAIL-study, we observed substantial intraindividual variability in midazolam pharmacokinetics in patients with obesity before and after weight loss over a short period of time. Accordingly, we performed a study in healthy volunteers without obesity (IntraCYP-study) where we showed a low- to moderate intraindividual variability in midazolam absolute bioavailability and systemic clearance on average, indicating a minor variability in CYP3A activity over time. However, a relevant number of the healthy volunteers displayed considerable intraindividual variability that should be considered when using midazolam to assess CYP3A activity. The data in the first paper also indicated that systemic midazolam clearance to a large degree reflected other processes than CYP3A metabolic capacity. Thus, we evaluated 4βOHC as an endogenous biomarker for CYP3A4 activity. In this paper, we showed that 4βOHC appears to reflect hepatic, but not intestinal, CYP3A4 activity, making it a valuable supplement in traditional phenotyping studies using probe drugs such as midazolam.