Zidovudine Transport within the Rabbit Brain during Intracerebroventricular Administration and the Effect of Probenecid

Abstract

The elimination of zidovudine (AZT) from cerebrospinal fluid (CSF), its distribution from CSF to brain tissue, and its transport from brain extracellular fluid (ECF) to plasma were studied during intracerebroventricular (i.c.v.) infusion in unanesthetized rabbits. The effect of probenecid (PBD) on these transport processes was also studied. The concentration of AZT in brain ECF was measured by microdialysis with retrodialysis calibration for in vivo recovery. Plasma and CSF were sampled and analyzed for AZT and PBD using HPLC. The elimination of AZT from CSF showed nonlinear characteristics as the i.c.v. infusion rate was increased to 1 mg/h kg. The estimated maximum transport capacity and dissociation constant were 3.5 micrograms/min kg and 127 micrograms/mL, respectively. The total linear elimination clearance from CSF was 0.0073 mL/min kg. The spatial distribution of AZT in brain during i.c.v. infusion was simulated using a mathematical model which describes diffusive solute transport in brain ECF and efflux across the blood-brain barrier. This analysis yielded a brain to plasma efflux rate constant of 0.040/min. This parameter and the elimination clearance from CSF decreased significantly by the end of an 8-hour period during which PBD was infused intravenously at a rate of 15 mg/h kg.

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

“…In addition, it has been reported that a probenecid-sensitive transport system influences zidovudine efflux in rats and rabbits (Takasawa et al, 1997;Wang et al, 1997). This system is not expected to be Bcrp1, because we have shown that probenecid does not inhibit Bcrp1-mediated transport of either zidovudine or abacavir .…”

“…We examined the effect of potent transporter inhibitors LY335979, Ko143, and GF120918 (selective P-gp, BCRP, and dual BCRP/P-gp inhibition, respectively) in the wild-type and Bcrp1 Ϫ/Ϫ mice. The effect of probenecid, a broadspectrum organic anion transport system inhibitor that has been shown to improve the CNS penetration of NRTIs, such as AZT, ddC, and ddI (Takasawa et al, 1997;Wang et al, 1997;Gibbs and Thomas, 2002), on the plasma concentration and brain penetration of abacavir in the wild-type and Bcrp1 Ϫ/Ϫ mice, was also determined. In addition, we examined the effect of Pluronic P85, a P-gp inhibitor (Batrakova et al, 2001), on abacavir disposition in wild-type mice.…”

P-glycoprotein-Mediated Active Efflux of the Anti-HIV1 Nucleoside Abacavir Limits Cellular Accumulation and Brain Distribution

“…6, C and D). AZT has been shown to be effluxed by a probenecid-sensitive transporter, and the baseline efflux seen in this study is possibly mediated by such a transporter (Wang et al, 1997). Moreover, overexpression of P-gp in the MDR1 cells had no effect on either the A-to-B or the B-to-A flux of AZT, indicating a lack of P-gp-mediated efflux.…”

Abcg2/Bcrp1 Mediates the Polarized Transport of Antiretroviral Nucleosides Abacavir and Zidovudine

“…Probenecidsensitive CNS distribution of AZT was previously reported in the rat (Takasawa et al, 1997), adult rhesus monkey (Cretton et al, 1991), and rabbit (Wong et al, 1993;Wang et al, 1997). The influence of probenecid on efflux transport of other NRTI, such as zalcitabine, didanosine, and tenofovir (Takasawa et al, 1997;Gibbs and Thomas, 2002;Mallants et al, 2005), has also been reported.…”