**3.2 Distribution**

Distribution of a drug may be affected by changes in body composition, such as changes in total body water and adipose tissue, which are not necessarily proportional to changes in total body weight. Plasma protein binding and tissue binding changes arising from changes in body composition with growth and development may also influence distribution (Buxton & Benet, 2011).

Prior to the absorption, drug is carried to organs and tissues through blood-circulation. Composition of body liquids and the drug's level of protein-binding affect the distribution level. Plasma albumin is a primer binding-place for drugs. This binding phenomenon delimits the amount of free drug in circulation, hence, preventing drug to attain at toxic levels (Çetinkaya &Tengir, 2006).

The amount of binding to plasma protein differs from one drug to another. Therefore, density and the amount of the drug that reached to the receptor zone are not proportional to dose. Neonatal albumin has lower binding capacity to some drugs (*Phenytoin*).

Should the active free drugs remain at high levels in blood, the chances for toxic effects to surface become more likely. The water amount in body is a significant parameter used to determine the highest attained drug density. The total water amount of premature infants constitutes the 80-85% of their total weight, whereas this ratio is 75% for interm infants, and it is at adult-like levels (50-60%) by the end of age two. Given the amount of total weight to adjust proportional dose levels, administering drugs that are water-soluble results in insufficient drug density in blood-plasma; thus, more appropriate doses are used for infants (Çetinkaya &Tengir, 2006).

The ability to metabolize drugs in newborns (especially premature infants) is quite limited due to physiological immaturity (Çetinkaya &Tengir, 2006).

Once metabolized, drugs transform into water-soluble compositions for excretion at kidneys. Most of this bio-transfer takes places in the liver. Two-to-three weeks from delivery, liver enzymes begins to maturate; at about the 4th week liver functions are fully developed and the excess drugs can be metabolized. If this period is not taken into account, the non-metabolized drugs begin to accumulate at toxic levels (Çetinkaya &Tengir, 2006).

Because the metabolism rate of an infant (and small child) is faster than an adult, certain drugs can be metabolized also faster. Another factor is the change in liver size. Fetal liver is the 4% of total weight in infants, while this is 2% for adults. This alone explains why many drugs are disposed more quickly, and, accordingly, why the children require medication in higher-doses (Çetinkaya &Tengir, 2006).

The volume of body liquids vary comparing to adults. Comparing to total weight, body liquids in children are more than they are in adults (Pala & Baktr, 2011).

The relative mass of fatty tissues and skeleton muscle tissues are less than those at adults. Especially fat-soluble drugs have greater distribution volume; they should be used in lower doses (Pala & Baktr, 2011).

The rate of drugs' protein binding is lower since the total protein concentration is lower than that in adults. Since the free drug concentration in the blood is higher, so is for the toxicity risk (Pala & Baktr, 2011).

The blood-brain barrier isn't fully developed. There is a risk for hypersensitivity against the drugs affecting the central (Pala & Baktr, 2011).
