TY - JOUR
T1 - The influence of intestinal lymphatic transport on the systemic exposure and brain deposition of a novel highly lipophilic compound with structural similarity to cholesterol
AU - Caliph, Suzanne Mary
AU - Faassen, Fried W
AU - Porter, Christopher John
PY - 2014
Y1 - 2014
N2 - OBJECTIVES:
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.
METHODS:
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.
KEY FINDINGS:
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.
CONCLUSION:
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.
AB - OBJECTIVES:
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.
METHODS:
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.
KEY FINDINGS:
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.
CONCLUSION:
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.
UR - http://onlinelibrary.wiley.com/doi/10.1111/jphp.12268/epdf
U2 - 10.1111/jphp.12268
DO - 10.1111/jphp.12268
M3 - Article
VL - 66
SP - 1377
EP - 1387
JO - Journal of Pharmacy and Pharmacology
JF - Journal of Pharmacy and Pharmacology
SN - 0022-3573
IS - 10
ER -