Two compartment model, Oral administration

After administration of a drug by oral route, its plasma concentration increases, reaches a maximum, then decreases, initially quickly, then more slowly.

Evolution of the plasma concentrations of a drug taken by oral route (2 compartment model)

Increasing curve 0 to Cmax, 1> 2 + 3 + 4	1 = Absorption (injection)
Cmax, 1 = 2 + 3 + 4	2 = Biotransformations
Decreasing curve 1 < 2 + 3 + (4)	3 = Elimination
Slope alpha, 2 + 3 + 4	4 = Transfer from C1 to C2
Slope beta, 2 + 3	5 = Transfer from C2 to C1

Evolution of plasma concentrations of a drug after repeated administrations:

When the interval of time separating two successive administrations of a drug is sufficiently long, at the time of the second administration, the drug is not present any more in the body.

The three factors to take into account in the case of repeated administrations of a drug are the administered dose, the frequency of administrations and the half-life of the drug.

Short half-life, not very frequent administrations

The duration of persistence of a drug in the body increases with the increase of  dose and half-life. When the interval between two successive administrations is long, there is no accumulation of the drug.

Plasma concentration of a drug after repeated administrations without accumulation

Long half-life or frequent administrations:

When the frequency of administration of a drug is sufficient or when its half-life is sufficiently long, there is a residual concentration of the drug at the time of its later administration. In this case, the repetition of its administrations at constant intervals leads to a progressive increase in its concentration until reaching a maximum concentration or steady state which is reached in approximately five half-lives. The administered dose remains constant whereas the quantity of product eliminated by unit of time rises, until compensating for the quantity supplied by each administration.

Plasma concentration of a drug after repeated administrations with accumulation - Min = residual concentration

Passage of drugs across membranes:

Before studying the passage of drugs across membranes it is necessary to recall the composition and structure of the membrane.

Composition and structure of membranes:

Plasma membrane which surrounds each cell consists of approximately 60% of phospholipids and 40% of protein.

Lipids:

The lipids entering the composition of membranes are amphipathic, they consist of molecules containing a polar head and a non polar or hydrophobic tail. They are primarily:

• glycerophospholipids (substituted glycerol).

• sphingolipids (i.e. derived from sphingosine which is an alcohol substituted by a fatty acid and a polar group). The sphingolipids are divided into three groups: sphingomyelins, cerebrosides and gangliosides.

• cholesterol consisting of a sterane  nucleus substituted by a polar group (OH) and a non polar flexible chain. Cholesterol, intercalated between other lipids, reinforces the membrane structure.

These amphipathic lipids (glycerophospholipids and sphingolipids) are naturally oriented to form a bilayer: polar groups located on both sides and the non polar tails in the middle.

The fluidity of the bilayer depends on temperature, but also on its composition. The unsaturated fatty acids which form less linear chains than the saturated fatty acids increase membrane fluidity.