Concentration-dependent effect of naringin on intestinal absorption of beta(1)-adrenoceptor antagonist talinolol mediated by p-glycoprotein and organic anion transporting polypeptide (Oatp).
OBJECTIVE
The purpose of this study is to clarify the impact of P-gp and Oatp on intestinal absorption of the beta(1)-adrenoceptor antagonist talinolol.


METHODS
P-gp-mediated transport was measured in LLC-PK1/MDR1 cells. Oatp-mediated uptake was evaluated with Xenopus oocytes expressing Oatp1a5. Rat intestinal permeability was measured by the in situ closed loop method. In vivo absorption was pharmacokinetically assessed by measuring plasma concentration after oral administration in rats.


RESULTS
In LLC-PK1/MDR1 cells, the permeability of talinolol was markedly higher in the secretory direction than in the absorptive one. The uptake of talinolol by Xenopus oocytes expressing Oatp1a5 was significantly increased compared with that by water-injected oocytes. Naringin inhibited talinolol uptake by Oatp1a5 (IC (50) = 12.7 microM). The reported IC (50) value of naringin for P-gp-mediated transport of talinolol is approximately 2,000 microM. Rat intestinal permeability of talinolol was significantly decreased in the presence of 200 microM naringin, but was significantly increased by 2,000 microM naringin. Similar results were obtained in in vivo absorption studies in rats.


CONCLUSIONS
The absorption behavior of talinolol can be explained by the involvement of both P-gp and Oatp, based on characterization of talinolol transport by Oatp1a5 and P-gp, and the effects of naringin.
Shirasaka
Yoshiyuki
Y
Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
Li
Yan
Y
Shibue
Yuta
Y
Kuraoka
Erika
E
Spahn-Langguth
Hildegard
H
Kato
Yukio
Y
Langguth
Peter
P
Tamai
Ikumi
I
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000502:physiology*; D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D032083:Citrus paradisi / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005260:Female; D044950:Flavanones / Q000302:isolation & purification / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects*; D018374:LLC-PK1 Cells; D008297:Male; D009865:Oocytes / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000096:biosynthesis / Q000502:physiology*; D011412:Propanolamines / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013552:Swine; D014982:Xenopus laevis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D044950:Flavanones; D029362:Organic Anion Transporters, Sodium-Independent; D011412:Propanolamines; C421143:Slco1a5 protein, rat; C011550:talinolol; C005274:naringin