ausblenden:
Schlagwörter:
MULTIDRUG-RESISTANCE; SPECIES-DIFFERENCES; GENE; BARRIER; PENETRATION;
CYP2D6; PHARMACOKINETICS; AMITRIPTYLINE; LOCALIZATION; POLYMORPHISMPsychiatry; P-glycoprotein (P-gp); ABCB1; Blood-brain barrier; Donepezil; abcb1ab
knock-out mice;
Zusammenfassung:
Polymorphisms in the drug transporter gene ABCB1 predict the treatment response of selected antidepressants and limit anticonvulsive medication's effectiveness. The ABCB1 locus encodes the energy-dependent transporter P-glycoprotein (P-gp) of the blood brain barrier (BBB), which serves as an efflux pump of its substrates in the expressing tissues of vertebrates. One experimental setup to determine a posteriori the P-gp substrate status is the use of the double abcbl ab knock-out (KO) mice model. Since so far, P-gp substrate status of donepezil, a cholinesterase inhibitor wildly used in Alzheimer's disease therapy was inconclusive, we performed subcutanous (s.c.), continuous injections over 11 days in double abcb1ab KO and P-gp competent wildtype (WT) mice. Both in brain and in testis concentrations of donepezil were significantly higher in P-gp deficient mice compared to WT controls (2.39 and 2.24 times respectively). In conclusion, in mice donepezil's brain bioavailability depends on P-gP.
