Correlation of Body Weight and Composition With Hepatic Activities of Cytochrome P450 Enzymes.

Abstract

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/m2 were obtained. Individual hepatic microsomes were prepared and activities of CYP3A, CYP2B6, CYP2C8, CYP2D6, CYP2C9, CYP2C19 and CYP1A2 were determined. The unbound intrinsic clearance (CLint,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 CLint,u values for CYP3A decreased with 5% with each 10% increase in body weight (r2 = 0.12, β = -0.558, p < 0.05). There were no correlations between body weight measures and CLint,u values for the other CYP enzymes investigated. These results indicate reduced hepatic metabolizing capacity of CYP3A substrates in patients with increasing body weight.

• Authors: Veronica Krogstad, Alexandra Peric, Ida Robertsen, Marianne K 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
• Journal: Journal of pharmaceutical sciences (J Pharm Sci) Vol. 110 Issue 1 Pg. 432-437 (01 2021) ISSN: 1520-6017 [Electronic] United States
• PMID: 33091408 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cytochrome P-450 Enzyme System
• Cytochrome P-450 CYP2C9
• Cytochrome P-450 CYP2D6
• Cytochrome P-450 CYP3A

Topics

• Body Weight
• Cytochrome P-450 CYP2C9
• Cytochrome P-450 CYP2D6
• Cytochrome P-450 CYP3A
• Cytochrome P-450 Enzyme System
• Humans
• Liver
• Microsomes, Liver