The influence of intestinal lymphatic transport on the systemic exposure and brain deposition of a novel highly lipophilic compound with structural similarity to cholesterol. (12th May 2014)

• Record Type: Journal Article
• Authors: Caliph, Suzanne M.; Faassen, Fried W.; Porter, Christopher J. H.
• Is Part Of: Journal of pharmacy and pharmacology. Volume 66:Number 10(2014:Oct.)
• Page Start: 1377
• Page End: 1387
• Publication Date: 2014-05-12
• Subjects: Pharmacy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/jphp.12268
• Languages: English
• ISSNs: 0022-3573

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <sec id="jphp12268-sec-0001" sec-type="section"> <title>Objectives</title> <p>To assess the role of intestinal lymphatic transport in the oral bioavailability and brain deposition of a highly lipophilic, centrally acting drug candidate (Org 49209) in comparison to cholesterol, a close structural analogue.</p> </sec> <sec id="jphp12268-sec-0002" sec-type="section"> <title>Methods</title> <p>The intestinal lymphatic transport of Org 49209 and cholesterol was assessed in lymph‐cannulated anaesthetised rats and total bioavailability evaluated in non‐lymph‐cannulated animals. Parallel groups were employed to examine the brain deposition of Org 49209 after intraduodenal and intraperitoneal administrations.</p> </sec> <sec id="jphp12268-sec-0003" sec-type="section"> <title>Key findings</title> <p>The contribution of intestinal lymphatic transport to total bioavailability was similar for Org 49209 and cholesterol (approximately 40% of the absorbed dose). However, the oral bioavailability of Org 49209 was significantly (fourfold) lower than cholesterol. Brain deposition of Org 49209 was similar after intraduodenal and intraperitoneal administration. Systemic exposure, however, was higher after intraduodenal administration and brain‐to‐plasma ratios were therefore reduced.</p> </sec> <sec id="jphp12268-sec-0004" sec-type="section"> <title>Conclusion</title> <p>The oral bioavailability of Org 49209 was significantly lower than that of its structural analogue cholesterol; however, intestinal lymphatic transport played a similar role in oral bioavailability for both compounds. Brain to plasma ratios were lower after intraduodenal versus intraperitoneal administration, suggesting that drug association with intestinal lymph lipoproteins may limit central nervous system access for highly lipophilic drugs.</p> </sec> </abstract>