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With permission from Springer Verlag.

^Calculated from Equations 5 and 12 of Keen.48 F is the factor by which plasma protein binding increases the time for which the free drug concentration exceeds any given value assuming the initial free drug concentration is the same in each case.

### With permission from Springer Verlag.

^Calculated from Equations 5 and 12 of Keen.48 F is the factor by which plasma protein binding increases the time for which the free drug concentration exceeds any given value assuming the initial free drug concentration is the same in each case.

the half-life is lengthened 2.74 times and in adults 5.75 times for a highly bound drug. The increase is dampened more effectively in newborns because the extracellular water accounts for a larger proportion of the body weight in newborns compared to adults (45% vs. 17%). The smaller difference in half-lives between newborn infants and adults for a drug distributed in total body water (1.47 vs. 1.66) is explained by similar reasoning.

For a 1-year-old child, the potential effect of protein binding on drug elimination by glomerular filtration and distributed in total body water, or in plasma water, should be approximately the same as for an adult because of the similarity of these compartments in these two age groups. On the other hand, extracellular water space does not reach the adult level by 1 year of age, so there is still a difference in elimination half-life as protein binding increases between a 1-year-old child and an adult. These relationships are graphically illustrated in Figure 4.2.

The effects described in Table 4.5 apply to a single dose of drug, but Keen's model48 also applies to the potential effects of protein binding on plasma drug concentration and elimination in response after repeated drug dosing (Table 4.6). The effects on single dosing (Table 4.5) and on repeated dosing (Table 4.6) follow a similar pattern. Notice that for a highly bound drug, there is a 50% decrease in the maximum blood level of the drug, and the minimum level of the free drug can decrease to zero between doses. As with single dosing, the greatest potential effects occur when the drug is confined to plasma water in both newborn and adult, but when it is distributed in extracellular water, or in total body water,

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