Zhang, Hongjian
(Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute)
,
Yao, Ming
(Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute)
,
Morrison, Richard-A.
(Schering-Plough Research Institute)
,
Chong, Sae-Ho
(Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute)
Tween 80 (Polysorbate 80) is a hydrophilic nonionic surfactant commonly used as an ingredient in dosing vehicles for pre-clinical in vivo studies (e.g., pharmacokinetic studies, etc.). Tween 80 increased apical to basolateral permeability of digoxin in Caco-2 cells suggesting that Tween 80 is an in ...
Tween 80 (Polysorbate 80) is a hydrophilic nonionic surfactant commonly used as an ingredient in dosing vehicles for pre-clinical in vivo studies (e.g., pharmacokinetic studies, etc.). Tween 80 increased apical to basolateral permeability of digoxin in Caco-2 cells suggesting that Tween 80 is an in vitro inhibitor of P-gp. The overall objective of the present study was to investigate whether an inhibition of P-gp by Tween 80 can potentially influence in vivo absorption of P-gp substrates by evaluating the effect of Tween 80 on the disposition of digoxin (a model P-gp substrate with minimum metabolism) after oral administration in rats. Rats were dosed orally with digoxin (0.2 mg/kg) formulated in ethanol (40％, v/v) and saline mixture with and without Tween 80 (1 or 10％, v/v). Digoxin oral AUC increased 30 and 61％ when dosed in 1 ％ and 10％ Tween 80, respectively, compared to control (P＜0.05). To further examine whether the increase in digoxin AUC after oral administration of Tween 80 is due, in part, to a systemic inhibition of digoxin excretion in addition to an inhibition of P-gp in the GI tract, a separate group of rats received digoxin intravenously (0.2 mg/kg) and Tween 80 (10％ v/v) orally. No significant changes in digoxin IV AUC was noted when Tween 80 was administered orally. In conclusion, Tween 80 significantly increased digoxin AUC and Cmax after oral administration, and the increased AUC is likely to be due to an inhibition of P-gp in the gut (i.e., improved absorption). Therefore, Tween 80 is likely to improve systemic exposure of P-gp substrates after oral administration. Comparing AUC after oral administration with and without Tween 80 may be a viable strategy in evaluating whether oral absorption of P-gp substrates is potentially limited by P-gp in the gut.
Tween 80 (Polysorbate 80) is a hydrophilic nonionic surfactant commonly used as an ingredient in dosing vehicles for pre-clinical in vivo studies (e.g., pharmacokinetic studies, etc.). Tween 80 increased apical to basolateral permeability of digoxin in Caco-2 cells suggesting that Tween 80 is an in vitro inhibitor of P-gp. The overall objective of the present study was to investigate whether an inhibition of P-gp by Tween 80 can potentially influence in vivo absorption of P-gp substrates by evaluating the effect of Tween 80 on the disposition of digoxin (a model P-gp substrate with minimum metabolism) after oral administration in rats. Rats were dosed orally with digoxin (0.2 mg/kg) formulated in ethanol (40％, v/v) and saline mixture with and without Tween 80 (1 or 10％, v/v). Digoxin oral AUC increased 30 and 61％ when dosed in 1 ％ and 10％ Tween 80, respectively, compared to control (P＜0.05). To further examine whether the increase in digoxin AUC after oral administration of Tween 80 is due, in part, to a systemic inhibition of digoxin excretion in addition to an inhibition of P-gp in the GI tract, a separate group of rats received digoxin intravenously (0.2 mg/kg) and Tween 80 (10％ v/v) orally. No significant changes in digoxin IV AUC was noted when Tween 80 was administered orally. In conclusion, Tween 80 significantly increased digoxin AUC and Cmax after oral administration, and the increased AUC is likely to be due to an inhibition of P-gp in the gut (i.e., improved absorption). Therefore, Tween 80 is likely to improve systemic exposure of P-gp substrates after oral administration. Comparing AUC after oral administration with and without Tween 80 may be a viable strategy in evaluating whether oral absorption of P-gp substrates is potentially limited by P-gp in the gut.
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제안 방법
Based on the observed systemic effect of Tween 80 on the digoxin clearance, it became 니nclea「whether the effect of Tween 80 on the oral AUC of digoxin is d니e to inhibit on of intestinal P-gp (thereby increasing absorption) or i가 ibi:ion of P-gp responsible for urinary and biliary clearc nee (thereby decreasing elimination) of digoxin or in comb nation of both, lb answer this question, the pharma cokinetics of intravenously dosed digoxin was monitored after an oral dose of vehicle containing 10% Tween 80. As summarized in Table II, orally administered Tween 80 did rot produced statistically significant difference in digox n IV AUC.
For detection, a Sciex API3000 LC/MS/MS system with an atmospheric pressure ionization (API) and electrospray inlet in the positive ion-multiple reaction monitoring mode was used. The ions monitored were: precursor-키기gd니ct ions of m/z 798.
성능/효과
The first study investigated the effect of Tween 80 on digoxin PK after oral administration in vehi이es containing Tween 80, and the results are summarized in Fig. 1 and Table I. 10% Tween 80 increased digoxin Cmax and AUC0-10 h by 161% and 61%, respectively. A similar trend was observed in the dosing vehicle containing 1% Tween 80, where digoxin Cmax and AUC0-10h increased by 163% and 30%, respectively.
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