Blood-Tissue Barriers

Drugs are transported in the blood todifferent tissues of the body. In order toreach their sites of action, they mustleave the bloodstream. Drug permea-tion occurs largely in the capillary bed,where both surface area and time avail-able for exchange are maximal (exten-sive vascular branching, low velocity offlow). The capillary wall forms theblood-tissue barrier. Basically, thisconsists of an endothelial cell layer anda basement membrane enveloping thelatter (solid black line in the schematicdrawings). The endothelial cells are“riveted” to each other by tight junc-tions or occluding zonulae (labelled Z inthe electron micrograph, top left) suchthat no clefts, gaps, or pores remain thatwould permit drugs to pass unimpededfrom the blood into the interstitial fluid.
The blood-tissue barrier is devel-oped differently in the various capillarybeds. Permeability to drugs of the capil-lary wall is determined by the structuraland functional characteristics of the en-dothelial cells. In many capillary beds,e.g., those of cardiac muscle, endothe-lial cells are characterized by pro-nounced endo- and transcytotic activ-ity, as evidenced by numerous invagina-tions and vesicles (arrows in the EM mi-crograph, top right).

Transcytotic activ-ity entails transport of fluid or macro-molecules from the blood into the inter-stitium and vice versa. Any solutestrapped in the fluid, including drugs,may traverse the blood-tissue barrier. Inthis form of transport, the physico-chemical properties of drugs are of littleimportance.In some capillary beds (e.g., in thepancreas), endothelial cells exhibit fen-estrations. Although the cells are tight-ly connected by continuous junctions,they possess pores (arrows in EM mi-crograph, bottom right) that are closedonly by diaphragms. Both the dia-phragm and basement membrane canbe readily penetrated by substances oflow molecular weight — the majority ofdrugs — but less so by macromolecules,e.g., proteins such as insulin (G: insulinstorage granules. Penetrability of mac-romolecules is determined by molecu-lar size and electrical charge.

Fenestrat-ed endothelia are found in the capillar-ies of the gut and endocrine glands.In the central nervous system(brain and spinal cord), capillary endo-thelia lack pores and there is little trans-cytotic activity. In order to cross theblood-brain barrier, drugs must diffusetranscellularly, i.e., penetrate the lumi-nal and basal membrane of endothelialcells. Drug movement along this pathrequires specific physicochemical prop-erties (p. 26) or the presence of a trans-port mechanism (e.g., L-dopa, p. 188).Thus, the blood-brain barrier is perme-able only to certain types of drugs.Drugs exchange freely betweenblood and interstitium in the liver,where endothelial cells exhibit largefenestrations (100 nm in diameter) fac-ing Disse’s spaces (D) and where neitherdiaphragms nor basement membranesimpede drug movement.

 Diffusion bar-riers are also present beyond the capil-lary wall: e.g., placental barrier of fusedsyncytiotrophoblast cells; blood: testi-cle barrier — junctions interconnectingSertoli cells; brain choroid plexus: bloodbarrier — occluding junctions betweenependymal cells.