EFFECT OF THE MDR1A P-GLYCOPROTEIN GENE DISRUPTION ON THE TISSUE DISTRIBUTION OF SDZ-PSC-833, A MULTIDRUG RESISTANCE-REVERSING AGENT, IN MICE

Citation
S. Desrayaud et al., EFFECT OF THE MDR1A P-GLYCOPROTEIN GENE DISRUPTION ON THE TISSUE DISTRIBUTION OF SDZ-PSC-833, A MULTIDRUG RESISTANCE-REVERSING AGENT, IN MICE, The Journal of pharmacology and experimental therapeutics, 285(2), 1998, pp. 438-443
Citations number
36
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Pharmacy
ISSN journal
0022-3565
Volume
285
Issue
2
Year of publication
1998
Pages
438 - 443
Database
ISI
SICI code
0022-3565(1998)285:2<438:EOTMPG>2.0.ZU;2-Z
Abstract
The involvement of mdr1a P-glycoprotein (P-gP) on the tissue distribut ion of the multidrug resistance-reversing agent SDZ PSC 833 was assess ed by use of mdr1a (-/-) mice. The mdr1a (-/-) and wild-type mdr1a (+/ +) mice received a 4-h constant-rate i.v. infusion (2 mu g/min) of [C- 14]SDZ PSC 833. Mice were sacrificed at 0, 0.5, 1, 2 and 4 h during in fusion and at 0.5, 1,3, 8 and 24 h after stopping the infusion. Blood and tissues were analyzed on total (C-14) and parental SDZ PSC 833 con centrations. Mdr1a (-/-) mice exhibited increased SDZ PSC 833 accumula tion in cerebrum, cerebellum and somewhat in testes and small intestin e compared with the wild-type mice. The difference between mdr1a (-/-) and (+/+) brain (cerebrum and cerebellum) penetration depended on SDZ PSC 833 blood concentrations, because this cyclosporin analog apparen tly governs its own brain penetration by inhibiting the P-glycoprotein pump in mdr1a (+/+) mice. Thus the mdr1a (-/-)/(+/+) ratio of brain c oncentrations tended to decrease and increase at high and low blood co ncentrations, respectively. These findings clearly demonstrate the int eraction of SDZ PSC 833 with the P-glycoprotein present at the blood-b rain barrier. The SDZ PSC 833 distribution in other mdr1a P-glycoprote in-expressed tissues, as well as its metabolism and elimination, was n ot affected by the mdr1a gene disruption. This suggests that factors o ther than mdr1a P-gP are involved in the disposition of this multidrug resistance-reversing agent.