title: Cytochromes P450 Inhibitory Excipient-Based Self-Microemulsions for the Improved Bioavailability of Protopanaxatriol and Protopanaxadiol: Preparation and Evaluation.
abstract: Protopanaxatriol and protopanaxadiol exhibit limited oral bioavailability due to the poor solubility and intestinal cytochromes P450-mediated metabolism. This study set out to develop a novel cytochromes P450 inhibitory excipient(s)-based self-microemulsion to encapsulate protopanaxatriol and protopanaxadiol so as to enhance thein vivobioavailability by inhibiting intestinal metabolism. After screening the inhibitory effect of pharmaceutical excipients on the cytochromes P450-mediated metabolism, two self-microemulsions, SME-1 and SME-2, with similar physicochemical properties were prepared by using either active inhibitory excipients or corresponding inactive excipients. The results showed that no significant difference existed in the profiles ofin vitrorelease, cellular uptake, and permeability in Caco-2 cells, andin vivolymphatic transport between self-microemulsion-1 and self-microemulsion-2. Thein vivopharmacokinetic experiments indicated that self-microemulsion-1 conferred to significantly higher absolute bioavailability of protopanaxatriol (19.55 %) and protopanaxadiol (100.07 %) than those of the free drug (2.21 % and 23.70 %, respectively) or of self-microemulsion-2 (4.95 % and 45.35 %, respectively). The present work demonstrated that the presence of cytochromes P450 inhibitory excipients in self-microemulsion-1 tended to inhibit intestinal cytochromes P450-mediated metabolism and subsequently improved the oral bioavailability of protopanaxatriol and protopanaxadiol.
authors.affiliation: Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, Haidian District, Beijing, P. R. China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Yang
authors.affiliation: Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, Haidian District, Beijing, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, Haidian District, Beijing, P. R. China.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Liu
authors.affiliation: Key Laboratory for Neurodegenerative Diseases (Capital Medical University), Ministry of Education, Beijing, P. R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Hu
authors.affiliation: Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, Haidian District, Beijing, P. R. China.
authors.forename: Ruile
authors.initials: R
authors.lastname: Pan
authors.affiliation: Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, Haidian District, Beijing, P. R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chang
authors.affiliation: Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, Haidian District, Beijing, P. R. China.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, Haidian District, Beijing, P. R. China.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Liao
mesh_terms: D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D004655:Emulsions; D005079:Excipients / Q000494:pharmacology*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000201:enzymology; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D012502:Sapogenins / Q000493:pharmacokinetics*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004655:Emulsions; D005079:Excipients; D012502:Sapogenins; C081552:protopanaxatriol; C062916:protopanaxadiol