Expression of P-glycoprotein and CYP3A4 along the porcine oral-gastrointestinal tract: implications on oral mucosal drug delivery.
OBJECTIVE
To characterize the expression of Pgp and CYP3A4 along the oral-gastrointestinal (GI) tract for understanding the potential roles of CY3A4 and Pgp in oral mucosal drug delivery.


METHODS
Porcine buccal mucosa, sublingual mucosa, esophagus and jejunum, ileum and colon tissues were used for studying the mRNA and protein expression of CYP3A4 and Pgp. mRNA and protein were determined using real-time quantitative polymerase chain reaction (PCR) and western blot, respectively. The expression levels of CYP3A4 and Pgp in different segments of oral-GI tract were compared.


RESULTS
Levels of Pgp mRNA were significantly lower (14-40 times lower) in buccal and sublingual mucosa than that in intestine. In contrast, higher levels of CYP3A4 mRNA were observed in the oral mucosa as compared to that in intestine, but the difference was not statistically different. The levels of Pgp protein along the oral-GI tract followed the order: sublingual ∼buccal ∼esophagus < jejunum ∼ileum ∼ colon while the expression of CYP3A4 protein in the oral mucosa was similar to that in intestine.


CONCLUSIONS
Expression of Pgp in oral mucosa is lower than that in intestine, while the expression of CYP3A4 in oral mucosa is similar to that in intestine. Because of lower Pgp in oral mucosa, oral mucosal drug delivery can be used as an alternative strategy to avoid the coordination of Pgp and CYP3A4 metabolism in drug absorption. However, CYP3A4-dependent metabolism may play a role in oral mucosal drug delivery as in per oral-GI absorption.
Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific , Stockton, CA , USA and.
Xiaoling
X
Gao
Shiladitya
S
Bhattacharya
William K
WK
Chan
Bhaskara R
BR
Jasti
Bala
B
Upadrashta
Xiaoling
X
Li
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism*; D000278:Administration, Buccal; D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism*; D041981:Gastrointestinal Tract / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D023421:Models, Animal; D009061:Mouth Mucosa / Q000378:metabolism; D065568:Oral Mucosal Absorption; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034421:Sus scrofa; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012333:RNA, Messenger; D051544:Cytochrome P-450 CYP3A