Investigation of the role of breast cancer resistance protein (Bcrp/Abcg2) on pharmacokinetics and central nervous system penetration of abacavir and zidovudine in the mouse.
Many anti-human immunodeficiency virus 1 nucleoside reverse-transcriptase inhibitors have low central nervous system (CNS) distribution due in part to active efflux transport at the blood-brain barrier. We have previously shown that zidovudine (AZT) and abacavir (ABC) are in vitro substrates for the efflux transport protein breast cancer resistance protein (Bcrp) 1. We evaluated the influence of Bcrp1 on plasma pharmacokinetics and brain penetration of zidovudine and abacavir in wild-type and Bcrp1-deficient (Bcrp1-/-) FVB mice. There was no difference in either area under the concentration-time profiles for plasma (AUC(plasma)) or brain (AUC(brain)) for zidovudine between the wild-type and Bcrp1-/- mice. The AUC(plasma) of abacavir was 20% lower in the Bcrp1-/- mice, whereas the AUC(brain) was 20% greater. This difference resulted in a 1.5-fold increase in abacavir brain exposure in the Bcrp1-/- mice. The effect of selective and nonselective transport inhibitors on the ABC brain/plasma ratio at a single time point was evaluated. 3-(6-Isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6, 7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indol-3-yl)-propionicacid tert-butyl ester (Ko143), N[4[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]-5-methoxy-9-oxo-10H-acridine-4-carboxamide (GF120918), probenecid, and Pluronic P85 increased abacavir plasma concentrations in the wild-type mice. Abacavir plasma concentrations in Bcrp1-/- mice were increased by (R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo (a,e)cyclopropa(c)cycloheptan-6-yl)-alpha-((5-quinoloyloxy)methyl)-1-piperazineethanol trihydrochloride (LY335979), GF120918, and probenecid, but not by Ko143. Brain/plasma concentration ratios in both the wild-type and Bcrp1-/- mice were increased by the P-glycoprotein inhibitors LY335979 and GF120918, but not by BCRP-selective inhibitors. These data indicate that deletion of Bcrp1 has little influence on the pharmacokinetics or brain penetration of AZT. However, for abacavir, deletion of Bcrp1 reduces plasma exposure and enhances brain penetration. These findings suggest that Bcrp1 does not play a significant role in limiting the CNS distribution of zidovudine and abacavir; however, brain penetration of abacavir is dependent on P-glycoprotein-mediated efflux.
Giri
Nagdeep
N
Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA.
Shaik
Naveed
N
Pan
Guoyu
G
Terasaki
Tetsuya
T
Mukai
Chisato
C
Kitagaki
Shinji
S
Miyakoshi
Naoki
N
Elmquist
William F
WF
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D015224:Dideoxynucleosides / Q000097:blood / Q000493:pharmacokinetics*; D051379:Mice; D018345:Mice, Knockout; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D015215:Zidovudine / Q000097:blood / Q000493:pharmacokinetics*; D000099227:Abacavir
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D015224:Dideoxynucleosides; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D000099227:Abacavir; C501412:Abcg2 protein, mouse