Diagnosing malabsorption with systemic lipid profiling: pharmacokinetics of pentadecanoic acid and triheptadecanoic acid following oral administration in healthy subjects and subjects with cystic fibrosis

Abstract

Objective: A Malabsorption Blood Test (MBT) is proposed as an alternative method to the 72-hour stool and dietary collection for assessing the degree of fat malabsorption in people with pancreatic insufficiency. The MBT consists of a simultaneous oral dose of pentadecanoic acid (PA), a free fatty acid, and triheptadecanoic acid (THA), a triglyceride with three heptadecanoic (HA) saturated fatty acids requiring hydrolysis by pancreatic lipase before HA can be intestinally absorbed. The aim of this study is to demonstrate the ability of MBT to detect fat malabsorption in healthy adult subjects using the pancreatic lipase (PL) inhibitor Orlistat (Xenical®), and in subjects with CF and PI while on and off routine pancreatic enzyme doses.

Materials and methods: The MBT with the PA and THA were delivered in a breakfast test meal (2.5 g PA and either 5 g or 8 g THA) to healthy adult subjects (ages 18 - 50 years, BMI 21 - 30) and to subjects with CF (> 12 years, FEV1% predicted > 40%), after a 12-hour fast and 24 hours without dairy foods. Serum levels of PA and HA were assessed by gas-liquid chromatography, from blood samples drawn prior to MBT and then hourly for 8 hours. For healthy subjects, the MBT was administered before and after Orlistat treatment, and in subjects with CF, both with subjects receiving routine pancreatic lipase treatment ("on enzyme") and also "off enzyme" treatment. Treatment groups were compared for baseline (C0) and maximum (Cmax) plasma concentrations of PA and HA over 8 hours: area under the curve (AUC) was calculated using linear trapezoid method. The ratio of HA to PA Cmax and AUC was also calculated and compared.

Results: For the healthy subjects (n = 15, 60% female, ages 21 - 49 years), absorption of HA was reduced 71% for Cmax (p < 0.001) and 65% for AUC (p = 0.001) after Orlistat treatment, and absorption of PA was unchanged. For subjects with CF (n = 6, 50% female, ages 13 - 19 years), absorption of HA was minimal with subjects "off enzymes" and increased significantly with subjects "on enzymes" while absorption of PA did not differ between groups. Enzyme administration resulted in increased Cmax HA/ PA ratios from 0.02 to 0.92 and from 0.05 to 0.73 in subjects with CF receiving 5.0 g and 8.0 g of THA, respectively. AUC HA/PA ratios showed similar increases.

Conclusions: In this pilot and feasibility proof-of-concept study, the MBT, utilizing the relative absorption of HA to PA, two odd-chained fatty acids, responds to changes in fat absorption in healthy subjects using a lipase inhibitor and in subjects with CF while on or off enzyme therapy. The MBT holds promise to provide a more accurate, specific and acceptable alternative to the 72-hour stool collection to quantify pancreatic-based fat malabsorption in a variety of clinical and research contexts.

Figures

Figure 1. Mean (A) PA and (B) HA concentration-time profiles resulting from 15 healthy subjects administered 2.5 g of PA and 8 g of THA in a MBT dosed with and without Orlistat.

Figure 2. Cmax (A) and AUC (B) HA/PA ratios by treatment for 15 healthy subjects enroled in the Orlistat study.

Figure 3. PA and HA concentration-time profiles resulting from 6 subjects with CF administered a MBT dosed with and without pancreatic enzymes. A: PA concentrations for 6 subjects dosed 2.5 g PA. B: HA concentrations for 3 subjects dosed 5 g of THA. C: HA concentrations for 3 subjects dosed 8 g of HA.

Figure 4. Cmax (A) and AUC (B) HA/PA ratios by treatment for 6 subjects with CF enroled in the CF Enzyme study. Solid lines with closed circles represent 3 subjects administered 5 g of THA. Dashed lines with open squares represent 3 subjects administered 8 g of THA.