**7.2. Tight junctions**

The gap junctions between cells in different cell types within a tissue can form channels for the passage of drugs between epithelial, endothelial, and mesothelial cells of the same tissue. These channels comprise of a group of proteins known as connexin. Cells in different tissues are however connected by tight junctions and these can impair transport between cells in different tissues. The tight junctions are dynamic structures, which normally regulate the trafficking of nutrients, medium sized compounds between cells, and form a regulated barrier in spaces between cells. There is need therefore to use drug absorption enhancers such as bile salts and long chain acyl-carnitines which act as Ca2+chelatorsand disrupt the tight junctions thereby improving transport across the junctions. Tight junctions are shown in Figure 2.

**7.4. Placental barrier**

during final stages of labour.

**8. Systemic availability of drugs**

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Time (minutes)

**Figure 4.** Plasma concentration versus time curves for different drug formulations

o o

Tmaxc Tmaxb Tmaxa

o <sup>a</sup> <sup>b</sup> <sup>c</sup>

The speed at which a particular drug is needed to reach the site of action will determine the type of formulation to use. Drugs with the same relative bioavailability and can be used to treat the same condition using either the same routes or dosages are known as bioequivalent drugs.

Increased risk of toxicity

Minimum effective concentration

Introduction to Biochemical Pharmacology and Drug Discovery

http://dx.doi.org/10.5772/52014

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[Plasma]

Cmaxa

Cmaxb

Cmaxc

The placental membrane limits the amount of maternal blood following through the placenta to the foetus and passive diffusion is the main mechanism of drug entry from the maternal blood to the foetus. The shortest time required for equilibration of a drug between mother and foetus is about ten minutes and this delay is useful as it can allow a mother to be anaesthetized

A drug will reach systemic arterial circulation only if it is absorbed from the GIT and if it escapes metabolism in the gut, liver, and lungs. When the concentration of the drug in plasma is measured at specified time intervals, it is possible to construct concentration versus time graph and hence be able to determine the extent of drug availability as shown in Figure 4.

The availability depends on both the extent of absorption and the extent of presystemic metabo‐ lism and comprises three aspects; Peak concentration (Cmax), Time taken to reach the peak (Tmax) and area under the curve (AUC)as shown in Figure 4. The Cmax and Tmax are measures of the rate of availability while AUC is a measure of the extent of availability (i.e. proportion of the admin‐ istered drug which reaches systemic circulation intact). For the three curves shown for the for‐ mulations a, b, and c; the AUC is the same, but the rate of availability is different in each case; a, has the lowest rate of availability followed by b, while c has the highest rate of availability.

Figure 2. Arrangement of epithelial cells with tight junctions **Figure 2.** Arrangement of epithelial cells with tight junctions

#### **7.3. Cerebrospinal fluid barrier (CSF)**  Epithelial cells which are in contact with the brain ventricular spaces form a barrier to the movement of drugs. These epithelial cells **7.3. Cerebrospinal fluid barrier (CSF)**

are connected by occluding zonulae (blood- brain barrier) as shown in Figure 3. The zonulae severely restrict the passage of most molecules between the bloodstream and the parenchyma of the central nervous system. Drug entry across this barrier is through either passive diffusion or carrier mediated transport.Only the lipid soluble drugs cross into the CSF from blood. Epithelial cells which are in contact with the brain ventricular spaces form a barrier to the movement of drugs. These epithelial cells are connected by occluding zonulae (blood- brain barrier) as shown in Figure 3. The zonulae severely restrict the passage of most molecules between the bloodstream and the parenchyma of the central nervous system. Drug entry across this barrier is through either passive diffusion or carrier mediated transport. Only the lipid soluble drugs cross into the CSF from blood.

between mother and foetus is about ten minutes and this delay is useful as it can allow a mother to be anaesthetized during final stages of labour. **Figure 3.** Epithelial cells with tight junctions as part of the blood brain barrier

**8. Systemic availability of drugs**  A drug will reach systemic arterial circulation only if it is absorbed from the GIT and if it escapes metabolism in the gut, liver, and lungs. When the concentration of the drug in plasma is measured at specified time intervals, it is possible to construct concentration versus time graph and hence be able to determine the extent of drug availabilityas shown in Figure 4. The availability depends on both the extent of absorption and the extent of presystemic metabolism and comprises three aspects; Peak concentration (Cmax), Time taken to reach the peak (Tmax) and area under the curve (AUC)as shown in Figure 4. The Cmax and Epithelial cells that separate the CSF from the brain are connected with tight junctions and are characterized by marked scarcity of pinocytic vesicles. However, the epithelial cells that lines the brain are not connected by occluding zonulae and therefore, there is unrestricted passage of drug molecules from CSF to the brain. Drugs like penicillin which are not much lipid-soluble and required in high concentrations for the treatment of brain abscesses are administered through intrathecal injections directly into the CFS.

Tmax are measures of the rate of availability while AUC is a measure of the extent of availability (i.e. proportion of the administered

the main mechanism of drug entry from the maternal blood to the foetus. The shortest time required for equilibration of a drug
