A. Tissue permeability of DRUG
1. Physico chemical Properties
Important physico chemical properties which influence drug distribution are Molecular weight, degree of Ionization & partition coefficient.
§ Almost all the drugs having mol wt. 500 to 600 daltons easily cross the capillary membrane to diffuse into the ECF. However penetration of drug into the cell from ECF is function of mol size , ionization constant & partition coefficient of the drug.
Most of the drugs are weak acids or bases & their degree of ionization depends upon pKa. All drugs that are ionized can’t permeate the cell membrane hence the distribution is limited for these type of drugs.
Only unionized drugs that are generally lipophillic can cross the cell membrane. Among the drugs having same o/w partition coefficient but differ in extent of drug Ionization, the drug which is less ionized is absorbed or have greater permeability than that of more ionized form.
Ex- Salicylic acid & phenobarbitone have same o/w Partition coefficient but phenobarbitone is more unionized and hence distributed rapidly.
2. Physiological barrier
There are certain barriers present into the body which restricts the permeability of the drug through the membrane. The selective substances can pass through this type of membranes.
Some important & specialized physiological barriers are
Simple capillary endothelial barrier-
Capillaries are microscopical blood vessels that creates the connection between arteries & veins. The blood is supplied from the heart into the arteries, from there into the arterioles & via capillaries into the venules. From the venules it is supplies to the veins & then again re enter into the heart. Hence flow of blood from arterioles to the venulez is called as microcirculation.
It has simple endothelium layerarranged on the basement membrane, in which no tunica interna, externa & media are present.
The transfer or exchange of the molecule can occur by diffusion, transcytosis & bulk flow, mainly by diffusion.
Drug Ionised or unionized with mol wt of 600 dalton can diffuse through the capillary endothelium into the interstitial fluid.
Only drug bound to the blod plasma can’t be moved because of large mol size
Simple cell membrane
As discussed, a cell membrane is selective permeable to the substances. Non polar substances which are lipid soluble can pass through the cell membrane, It means the drug which are lipid soluble can diffuse through the cell membrane but water soluble substances can’t pass through it. So they are made up in such a way that they act on the receptor present on the cell surface and shows its therapeutic activity through secondary messenger which are responsible for different cellular activity.
Blood Brain Barrier (BBB)
Brain is very sensitive organ of the body, it requires oxygen & glucose for its regular function.
The endothelium of the brain capillaries are joined by tight junction described by “Paul”. He injected dye which can stain most of the cells of the body but fails to stain cells of brain Which concludes that brain capillaries are made up of specialized endothelial barrier. By this experiment we conclude that BBB is made of Brain capillary endothelial and pericapillary Glial cells.
The brain walls are impermeable to many drugs, including many anticancer drugs given for the treatment of Brain tumor. These type of drugs are lipid soluble still they are restricted by BBB. This is because of presence of astrocytes which act as supporting cells by forming a solid support around the blood capillaries and also the gap between 2 endothelial cells is very minimal.
Thus the drug molecule can’t be passed through the gaps between the cells but it has to pass through the cell cytosol. For ex: insulin passes through the cells by pinocytosis into the brain but can’t be passed through the gaps between the cells.
In addition, efflux carrier presents in the brain blood capillary endothelial cell and they have the capacity to remove the drugs molecules from the CNS.
o Main efflux carriers like P-glycoproten and OATP.these efflux tranpoters are use full for maintaining the conc. of drug into the tissue like GIT, LIVER, KIDNEY ,BBB, in which different isoenzymes are present .In these tissues, the level of drug conc. is low then desired quantity, so therapeutic effect is decreased. If such type of drug are not reached to site of action or such tissues, more drug is concentrated in plasma and leads to toxicity.
Ex-HIV proteases have less effect on CNS.
Drug molecule also leaving the CNS by the diffusion or by archanoid villi, efflux transporters also present in choroid plexus removing the drug to the blood from CNS.
Dopamine can’t cross the BBB, but its precursor levo dopa can, used in Parkinsonism. Actually, this L-dopa is converted to dopamine in periphery. But if given with carbidopa, if inhibits the conversion of L-dopa to dopamine and maximum L-dopa is present for penetration into brain.
Some enzyme also present in the capillary walls of brain, which don’t allow adrenaline or nor adrenaline, acetyl choline into the brain. It includes enzymes like MAO, choline esterase.
The drugs which induce the inflammation of the brain cell cause the increased in the permeability of BBB. Ex- penicillin given by IV route used to treat bacterial meningitis. Some peptide like bradykinin and enkaphalins increased BBB permeability used in the chemotherapy against brain tumor.
Cerbro spinal fluid barrier ( CSF barrier)
CSF is the colour less liquid, it contains glucose and other chemical needed for nourishment of the neurons. It presents in the subarchanoid space
It formed in the choroids plexuses of the each lateral ventricle, made up of capillaries which are covered by the ependymal cells that form CSF by filtration and secretion. These cells allowed selective substances to pass through the membrane. around 120 ml of CSF is present
The CSF returned to the circulation by flap valves these valves are opened when the hydrostatic pressure in subarchanoid space is greater than that in venous sinuses.
The entry of the drug in to the CSF barrier is depending upon the ionization of the drug and o/w partition co-efficient.
The drug which are non-ionized and has higher o/w partition co-efficient can pass the barrier easily. But those which are ionized in to the blood the ph can’t penetrate it.
Placental barrier
Fetal and maternal blood supply is not directly connected with each other. The blood supply b/w them is occur by placenta, a barrier around the embryo which is connected by umbilical cord with the maternal circulation
There are number of tissue layers made up of trophoblast cell and endothelium which constitute the placental barrier. During, early pregnancy the thickness of placenta is 25µm and in the late time it’s reduce to 2µm.
The drug molecule are easily pass through the placenta then compared to BBB, by carrier mediated transport essential neutrient,O2-CO2 and water are also transport through it.
Blood testis barrier ( BT barrier)
In the seminiferous tubules where sperm is produced along with spermatogenic cells, there are sertoli cells (sustanacular cells) present which extend from the basement membrane to lumen of the tubule.
These sertoli cells joined with the tight junction with each other. And forms bld – testis barrier they prevent immune response of the body to sperm cell.
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