title: Tween 20 increases intestinal transport of doxorubicin in vitro but not in vivo.
abstract: The chemotherapeutic drug substance doxorubicin has been reported to be a substrate of P-gp, which induces a barrier for oral administration and leads to a bioavailability of 3% in male Sprague Dawley rats. Literature studies have reported increased transport of P-pg substrates, like digoxin, when co-administered with P-gp inhibitors (non-ionic surfactants) in vitro and in vivo . The aim of the present study was thus to investigate if different non-ionic surfactants would have a similar effect on the in vitro and in vivo absorption of doxorubicin. This was investigated in vitro in Caco-2 cells and by oral co-administration of doxorubicin together with tween 20 to male Sprague Dawley rats. 200 μM (0.025%) tween 20 increased the intestinal absorptive permeability of doxorubicin in vitro by 48 ± 4% from 8.8 × 10(-6)cm/s to 13.0 × 10(-6)cm/s. Further, the efflux ratio was reduced from 2.2 ± 0.06 to 1.2 ± 0.03 (n=3-7). In vivo, co-administration of doxorubicin and 0-25% tween 20 did not yield detectable doxorubicin plasma concentrations, probably due to extensive intestinal metabolism. In conclusion, the present study demonstrated that non-ionic surfactants increased the transport of doxorubicin in vitro, most likely by inhibition of the efflux activity. However, this effect was not transferable to the in vivo situation.
authors.affiliation: Drug Transporters in ADME, Department of Pharmacy, Faculty of Health and Medical Sciences, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Amal
authors.initials: A
authors.lastname: Al-Saraf
authors.affiliation: Drug Transporters in ADME, Department of Pharmacy, Faculty of Health and Medical Sciences, Universitetsparken 2, DK-2100 Copenhagen, Denmark; Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, DK-2500 Valby, Denmark.
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark. Electronic address: cun@sdu.dk.
authors.forename: Carsten Uhd
authors.initials: CU
authors.lastname: Nielsen
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D011136:Polysorbates / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D011136:Polysorbates; D004317:Doxorubicin
keywords: Caco-2 cells; Doxorubicin; In vivo; Inhibitor; P-gp; Rats; Surfactants