title: The limited intestinal absorption via paracellular pathway is responsible for the low oral bioavailability of doxorubicin.
abstract: 1. Doxorubicin exhibited dose-independent pharmacokinetics after intravenous (5-20 mg/kg) and oral (20-100 mg/kg) administration to rats. Nearly all (82.1-99.7%) of the orally administered doxorubicin remained unabsorbed, and the hepatic first-pass extraction ratio and oral bioavailability of doxorubicin were approximately 0.5% and 1%, respectively. Based on these results, it is likely that the primary factor responsible for the low oral bioavailability of doxorubicin is the limited intestinal absorption, rather than the CYP3A4-mediated first-pass metabolism. 2. Moreover, the in vitro transport and cellular uptake studies using Caco-2 cell monolayers have revealed that doxorubicin crosses the intestinal epithelium primarily via the paracellular pathway (accounting for 85.6% of the overall absorptive transport) probably due to its physicochemical properties (hydrophilic cation; pKa = 9.67, log P = -0.5). These results suggest that P-glycoprotein (P-gp)-mediated efflux activity does not play a significant role in limiting the intestinal absorption of doxorubicin, attenuating the absorptive transport by only 5.56-13.2%. 3. Taken together, the present study demonstrated that the limited and paracellular intestinal absorption of doxorubicin was a major factor responsible for its low oral bioavailability, restricting the role of CYP3A4-mediated first-pass metabolism and P-gp-mediated efflux.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Ji-Eon
authors.initials: JE
authors.lastname: Kim
authors.forename: Hyun-Jong
authors.initials: HJ
authors.lastname: Cho
authors.forename: Jung Sun
authors.initials: JS
authors.lastname: Kim
authors.forename: Chang-Koo
authors.initials: CK
authors.lastname: Shim
authors.forename: Suk-Jae
authors.initials: SJ
authors.lastname: Chung
authors.forename: Min-Ho
authors.initials: MH
authors.lastname: Oak
authors.forename: In-Soo
authors.initials: IS
authors.lastname: Yoon
authors.forename: Dae-Duk
authors.initials: DD
authors.lastname: Kim
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D001682:Biological Availability; D018938:Caco-2 Cells; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004317:Doxorubicin / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A