Correlation of Body Weight and Composition With Hepatic Activities of Cytochrome P450 Enzymes
Veronica Krogstad, Alexandra Peric, Ida Robertsen, Marianne Kristiansen Kringen, Maria Vistnes, Jøran Hjelmesæth, Rune Sandbu, Line Kristin Johnson, Philip Carlo Angeles, Rasmus Jansson‐Löfmark, Cecilia Karlsson, Shalini Andersson, Anders Åsberg, Tommy B. Andersson, Hege Christensen
Abstract
Cytochrome P450 (CYP) Drug metabolizing enzyme(s) First-pass metabolism Hepatic metabolism Human liver microsomes Phase I metabolism a b s t r a c t Obesity is associated with comorbidities of which pharmacological treatment is needed. Physiological changes associated with obesity may influence the pharmacokinetics of drugs, but the effect of body weight on drug metabolism capacity remains uncertain. The aim of this study was to investigate ex vivo activities of hepatic drug metabolizing CYP enzymes in patients covering a wide range of body weight. Liver biopsies from 36 individuals with a body mass index (BMI) ranging from 18 to 63 kg/m 2 were obtained. Individual hepatic microsomes were prepared and activities of CYP3A, CYP2B6, CYP2C8, CYP2D6, CYP2C9, CYP2C19 and CYP1A2 were determined. The unbound intrinsic clearance (CL int,u ) values for CYP3A correlated negatively with body weight (r 0.43, p < 0.01), waist circumference (r 0.47, p < 0.01), hip circumference (r 0.51, p < 0.01), fat percent (r 0.41, p < 0.05), fat mass (r 0.48, p < 0.01) and BMI (r 0.46, p < 0.01). Linear regression analysis showed that CL int,u values for CYP3A decreased with 5% with each 10% increase in body weight (r 2 0.12, b 0.558, p < 0.05).