The Pharmacokinetics of the CYP3A Substrate Midazolam in Morbidly Obese Patients Before and One Year After Bariatric Surgery

Abstract

PurposeBariatric surgery is nowadays commonly applied as treatment for morbid obesity (BMI > 40 kg/m2). As information about the effects of this procedure on a drug’s pharmacokinetics is limited, we aimed to evaluate the pharmacokinetics of CYP3A probe substrate midazolam after oral and intravenous administration in a cohort of morbidly obese patients that was studied before and 1 year post bariatric surgery.MethodsTwenty morbidly obese patients (aged 26–58 years) undergoing bariatric surgery participated in the study of which 18 patients returned 1 year after surgery. At both occasions, patients received 7.5 mg oral and 5 mg intravenous midazolam separated by 160 ± 48 min. Per patient and occasion, a mean of 22 blood samples were collected. Midazolam concentrations were analyzed using population pharmacokinetic modeling.ResultsOne year after bariatric surgery, systemic clearance of midazolam was higher [0.65 (7%) versus 0.39 (11%) L/min, mean ± RSE (P < 0.01), respectively] and mean oral transit time (MTT) was faster [23 (20%) versus 51 (15%) minutes (P < 0.01)], while oral bioavailability was unchanged (0.54 (9%)). Central and peripheral volumes of distribution were overall lower (P < 0.05).ConclusionsIn this cohort study in morbidly obese patients, systemic clearance was 1.7 times higher 1 year after bariatric surgery, which may potentially result from an increase in hepatic CYP3A activity per unit of liver weight. Although MTT was found to be faster, oral bioavailability remained unchanged, which considering the increased systemic clearance implies an increase in the fraction escaping intestinal first pass metabolism.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-015-1752-9) contains supplementary material, which is available to authorized users.

The influence of bariatric surgery on oral drug bioavailability in patients with obesity: A systematic review

“…RYGBP was the predominant surgical procedure (n = 18) . In one study, BPD was investigated as the surgical procedure, while two studies investigated BPD‐DS, six studied SG, and one included jejunoileostomy …”

“…Midazolam undergoes hydroxylation via both intestinal and hepatic CYP3A and is the most commonly used probe drug to investigate in vivo CYP3A activity . The effects on midazolam pharmacokinetics were explored in three of the studies that make up this systematic review . In one of these studies, absolute bioavailability and clearance were assessable because of a combined oral and intravenous administration of midazolam .…”

“…The effects on midazolam pharmacokinetics were explored in three of the studies that make up this systematic review . In one of these studies, absolute bioavailability and clearance were assessable because of a combined oral and intravenous administration of midazolam . Midazolam clearance increased 1 year after surgery, whereas the absolute bioavailability ( F total ) remained unchanged.…”

Physiological and pharmacokinetic effects of multilevel caging on Sprague Dawley rats under ketamine-xylazine anesthesia

“…In our pharmacokinetic evaluation, we noted a peak in norketamine at 60 min in the SDC rats, possibly justified by a possible saturation of the hepatic enzymes and most likely associated with a greater depth of anesthesia. Cytochrome P450 expression and function are influenced by obesity levels, such as CYP3A hepatic expression levels are increased in high-fat fed Sprague-Dawley rats [14], whereas decreased activity has previously been linked to obesity in humans [4]. In addition, liver transcriptomics analysis of mouse induced obesity models revealed a global dysregulation of Cyp genes, most notably in the Cyp3a and Cyp2c families [11].…”

Sedation Challenges

“…A subsequent matched cohort study from the same group showed that RYGB patients required higher doses of sedation during EGD than the non-RYGB with similar age, gender and BMI [31]. Authors hypothesized that these findings could be due to an improvement in liver function after gastric bypass, which resulted in an improvement in liver metabolism of fentanyl and midazolam, which subsequently led to increased requirement of both sedatives during EGD [32–33]. …”