Biomaterial Database

Mechanisms by which 2',3'-dideoxyinosine (ddI) crosses the guinea-pig CNS barriers; relevance to HIV therapy. 2003

J E Gibbs, and P Jayabalan, and S A Thomas

Centre for Neuroscience, Guy's King's and St Thomas' School of Biomedical Science, King's College London, Guy's Hospital Campus, London Bridge, London SE1 1UL, UK.

The influence of transport mechanisms at the blood-brain barrier (BBB) and blood-CSF barrier (choroid plexus) on the CNS distribution of anti-human immunodeficiency virus (HIV) drugs was examined using guinea-pig brain perfusion and incubated choroid plexus models. 2',3'-dideoxyinosine (ddI) passage across the BBB was demonstrated to be via non-saturable (Kd = 0.22 +/- 0.3 microL/min/g) and saturable (Km = 20.1 +/- 15.0 microm, Vmax = 6.5 +/- 2.1 pmol/min/g) processes. Cross competition studies implicated an equilibrative nucleoside transporter in this influx. The brain distribution of ddI was unchanged in the presence of additional nucleoside reverse transcriptase inhibitors (NRTIs). ddI transport from blood into choroid plexus was demonstrated to involve an organic anion transporting polypeptide 2-like transporter. The NRTIs, abacavir, 3'-azido 3'-deoxythymidine and (-)-beta-L-2',3'-dideoxy-3'-thiacytidine, competed with ddI for transporter binding sites at the choroid plexus, altering the tissue concentration of ddI. This has clinical implications as the choroid plexus is a site of HIV replication, and suboptimal CNS concentrations of anti-HIV drugs could result in neurological complications. Furthermore, this may promote the selection of drug resistant variants of HIV within the CNS, which could re-infect the periphery and lead to HIV therapy failure. This study indicates that understanding drug interactions at the transporter level could prove valuable when selecting drug combinations to treat HIV within the CNS.

UI	MeSH Term	Description	Entries
D008353	Mannitol	A diuretic and renal diagnostic aid related to sorbitol. It has little significant energy value as it is largely eliminated from the body before any metabolism can take place. It can be used to treat oliguria associated with kidney failure or other manifestations of inadequate renal function and has been used for determination of glomerular filtration rate. Mannitol is also commonly used as a research tool in cell biological studies, usually to control osmolarity.	(L)-Mannitol,Osmitrol,Osmofundin
D010477	Perfusion	Treatment process involving the injection of fluid into an organ or tissue.	Perfusions
D011339	Probenecid	The prototypical uricosuric agent. It inhibits the renal excretion of organic anions and reduces tubular reabsorption of urate. Probenecid has also been used to treat patients with renal impairment, and, because it reduces the renal tubular excretion of other drugs, has been used as an adjunct to antibacterial therapy.	Benecid,Benemid,Benuryl,Pro-Cid,Probecid,Probenecid Weimer
D001812	Blood-Brain Barrier	Specialized non-fenestrated tightly-joined ENDOTHELIAL CELLS with TIGHT JUNCTIONS that form a transport barrier for certain substances between the cerebral capillaries and the BRAIN tissue.	Brain-Blood Barrier,Hemato-Encephalic Barrier,Barrier, Blood-Brain,Barrier, Brain-Blood,Barrier, Hemato-Encephalic,Barriers, Blood-Brain,Barriers, Brain-Blood,Barriers, Hemato-Encephalic,Blood Brain Barrier,Blood-Brain Barriers,Brain Blood Barrier,Brain-Blood Barriers,Hemato Encephalic Barrier,Hemato-Encephalic Barriers
D001921	Brain	The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.	Encephalon
D001923	Brain Chemistry	Changes in the amounts of various chemicals (neurotransmitters, receptors, enzymes, and other metabolites) specific to the area of the central nervous system contained within the head. These are monitored over time, during sensory stimulation, or under different disease states.	Chemistry, Brain,Brain Chemistries,Chemistries, Brain
D002199	Capillary Permeability	The property of blood capillary ENDOTHELIUM that allows for the selective exchange of substances between the blood and surrounding tissues and through membranous barriers such as the BLOOD-AIR BARRIER; BLOOD-AQUEOUS BARRIER; BLOOD-BRAIN BARRIER; BLOOD-NERVE BARRIER; BLOOD-RETINAL BARRIER; and BLOOD-TESTIS BARRIER. Small lipid-soluble molecules such as carbon dioxide and oxygen move freely by diffusion. Water and water-soluble molecules cannot pass through the endothelial walls and are dependent on microscopic pores. These pores show narrow areas (TIGHT JUNCTIONS) which may limit large molecule movement.	Microvascular Permeability,Permeability, Capillary,Permeability, Microvascular,Vascular Permeability,Capillary Permeabilities,Microvascular Permeabilities,Permeabilities, Capillary,Permeabilities, Microvascular,Permeabilities, Vascular,Permeability, Vascular,Vascular Permeabilities
D002250	Carbon Radioisotopes	Unstable isotopes of carbon that decay or disintegrate emitting radiation. C atoms with atomic weights 10, 11, and 14-16 are radioactive carbon isotopes.	Radioisotopes, Carbon
D002490	Central Nervous System	The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges.	Cerebrospinal Axis,Axi, Cerebrospinal,Axis, Cerebrospinal,Central Nervous Systems,Cerebrospinal Axi,Nervous System, Central,Nervous Systems, Central,Systems, Central Nervous
D002831	Choroid Plexus	A villous structure of tangled masses of BLOOD VESSELS contained within the third, lateral, and fourth ventricles of the BRAIN. It regulates part of the production and composition of CEREBROSPINAL FLUID.	Chorioid Plexus,Plexus Choroideus,Choroideus, Plexus,Plexus, Chorioid,Plexus, Choroid