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/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 ¼ À0.43, p < 0.01), waist circumference (r ¼ À0.47, p < 0.01), hip circumference (r ¼ À0.51, p < 0.01), fat percent (r ¼ À0.41, p < 0.05), fat mass (r ¼ À0.48, p < 0.01) and BMI (r ¼ À0.46, 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 ¼ 0.12, b ¼ À0.558, p < 0.05). There were no correlations between body weight measures and CL int,u values for the other CYP enzymes investigated. These results indicate reduced hepatic metabolizing capacity of CYP3A substrates in patients with increasing body weight.

Short‐ and long‐term effects of body weight loss following calorie restriction and gastric bypass on CYP3A‐activity – a non‐randomized three‐armed controlled trial

“…11,44 Further, the present study supports previous findings of an inverse relationship between BMI and oral clearance of CYP3A substrates (Figure 3c). 10,12,13 Given that we assessed both absolute bioavailability and clearance, we can argue that the negative association between BMI and oral clearance is explained by both higher bioavailability and clearance with higher body weight, but that the effect on bioavailability was greater. The protein quantification in the present study supports previous findings of a lower hepatic CYP3A expression and activity in patients with severe obesity 12,13 and in patients with NAFLD (Figure 3f,h).…”

“…For patients undergoing RYGB, small intestinal and hepatic biopsies were obtained on the day of surgery, as previously described. 13,25 Hepatic biopsies were also obtained from the control group during cholecystectomy. 13 Patients abstained from food and drugs from 10:00 p.m. the evening before all pharmacokinetic investigations.…”

“…13,25 Hepatic biopsies were also obtained from the control group during cholecystectomy. 13 Patients abstained from food and drugs from 10:00 p.m. the evening before all pharmacokinetic investigations. On the study day, patients met at 07:30 a.m. for blood sampling, before 1.5 mg oral midazolam syrup was administered followed by 1.0 mg intravenous midazolam 4 h later.…”

Development and Evaluation of a Virtual Population of Children with Obesity for Physiologically Based Pharmacokinetic Modeling

“…Dashed lines represent the lines of unity for reference, and blue lines represent a linear regression passing through the origin for better visualization of misspecification. The slope of this regression line is 1.26, 1.22, 1.20, and 1.18 for (a-d), respectively enzymes in adults, such evidence is lacking in children with obesity [36,37]. Few clinical studies are reported in children with obesity determining changes in metabolism using in vivo data, and those that exist conflict with known changes in adults with obesity [38], possibly owing to lower rates of comorbidities in children.…”

Stability investigations of cytochrome P450 (CYP) enzymes immediately after death in a pig model support the applicability of postmortem hepatic CYP quantification

“…Therefore, information regarding CYP levels in subpopulations is needed. There are numerous examples of subpopulations with altered CYP levels, to mention a few: Obese have reduced CYP3A activity with increasing bodyweight 4 ; Pregnant have increased activity of CYP2D6 and CYP3A4 and reduced CYP1A2 activity 5 ; Individuals suffering from cirrhosis have markedly reduced activity of CYP1A2 and CYP3A4. 6 …”