Association between low body weight and cytochrome P‐450 enzyme activity in patients with anorexia nervosa

Abstract

Very little is known to which extent severe underweight could affect cytochrome P‐450 (CYP) enzyme activity. In this study, 24 patients with anorexia nervosa at two occasions ingested single oral doses of five test drugs known to be metabolized by CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, respectively. A mixed model analysis was used to evaluate the effect of changes in body mass index (BMI) on the metabolic activities of these enzymes. The primary end point was the change in drug/metabolite ratio of each of the test drugs per kg/m2 change in BMI. With increasing BMI, the metabolic activity of CYP3A4 decreased (change in the CYP3A4 drug/metabolite ratio per unit change in BMI = 0.056; 95% confidence interval [CI] 0.011 to 0.102; P = .017). For CYP1A2, increasing BMI increased the metabolic activity with borderline significance (change in the CYP1A2 drug/metabolite ratio per unit change in BMI = –0.107; CI –0.220 to 0.005; P = .059). For CYP2C9, CYP2C19, and CYP2D6, no significant changes were seen. The clinical impact of these findings for drug treatment in patients with anorexia nervosa and other severely underweight patients needs to be further studied by examining the pharmacokinetics of specific drugs. This might be particularly relevant for drugs metabolized by CYP1A2 and/or CYP3A4.

Short‐ and long‐term effects of body weight, calorie restriction and gastric bypass on CYP1A2, CYP2C19 and CYP2C9 activity

“…CYP1A2‐mediated metabolism was not significantly different in patients with obesity and normal to overweight controls, which is in line with previous studies 13,14,45 . Although clearance by CYP1A2 seems to be similar in individuals with different body weights, CYP1A2‐mediated metabolism increased from baseline to week 9 in the diet group.…”

“…This difference diminished over time as CYP2C9‐mediated metabolism decreased significantly in the RYGB group after 3 weeks of LED, before stabilizing, whereas no changes were seen in the diet group. Other studies have not provided evidence of an altered CYP2C9‐mediated metabolism in different body weight ranges or following bariatric surgery 13,42,45 …”

“…line with previous studies. 13,14,45 Although clearance by CYP1A2 seems to be similar in individuals with different body weights, CYP1A2-mediated metabolism increased from baseline to week 9 in the diet group. This was not observed in the RYGB group, despite a similar weight loss, possibly due to unknown surgery-specific effects counteracting the true effect of weight loss on CYP1A2-mediated metabolism.…”

The Impact of Diet and Exercise on Drug Responses

“…The metabolic activity of CYP3A4 decreased, while CYP1A2 increased at a higher BMI. CYP2C9, CYP2C19 and CYP2D6 remained unaltered [ 32 ], indicating that CYP3A4 substrates, such as statins or Cyp1A2 substrates like theophylline, might show differences in their efficacy or toxicity, respectively. A further study supported these data showing higher CYP3A4 activity in underweight patients in comparison to normal-weight controls [ 33 ].…”

Perampanel overdose in low body mass index patients with epilepsy: a case report and review of the literature

“…The isoenzyme CYP3A4 is considered to be primarily involved in the metabolism of PER [ 11 ]. In a recent study on the correlation between body weight and CYP3A activity, [ 12 ] Sandvik et al reported that the enzyme activity of CYP3A4 was higher in patients with anorexia nervosa compared to a control group consisting of individuals with normal weight, and that CYP3A4 activity was negatively correlated with body weight [ 13 ]. Also, CYP3A4 activity was found to decrease with increasing body weight in healthy volunteers [ 14 ].…”