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+73.2

a Reproduced from S. Ozeki and K. Tejima, Chem. Pharm. Bull., 22, 1297 (1974).

a Reproduced from S. Ozeki and K. Tejima, Chem. Pharm. Bull., 22, 1297 (1974).

drugs such as digoxin and so act as a depot. Concentrations of 1.2 ± 0.8, 11.3 ± 4.9 and 77.7 ± 43.3 ng cm 3 have been reported for digoxin in plasma, skeletal muscle and cardiac muscle, respectively. Differences in the bioavailability of two antibiotics following intramuscular administration have been ascribed to differences in protein binding. Dicloxa-cillin, 95% bound to protein, is absorbed more slowly from muscle than ampicillin, which is bound only to the extent of 20%.

Drug binding often changes with drug concentration and with protein concentration. On increasing the drug/protein ratio, saturation of some sites can occur and there may be a decrease in binding (as indicated by total percentage). Hence the importance of determining binding at realistic albumin concentrations (about 40 g dm 3). There may be more than one binding site for a drug.

In determining the pharmacological importance of protein binding, several factors have to be considered. If drug molecules not bound to plasma protein are freely distributed throughout the body, on leaving the blood they enter a volume thirteen times as large as the plasma volume. Entry into the cerebrospinal fluid (CSF) depends on the concentration of free, diffusible drug in the plasma. Sulfanilamide enters CSF faster than sulfa-methoxypyridazine because less is bound to serum albumin. Such binding factors may override the intrinsic lipophilicities, which in some cases may suggest a different order of penetration from that observed.

When binding occurs with high affinity and the total amount of drug in the body is low, drug will be present almost exclusively in the plasma. Drugs with lower association constants (K q 106 or 107) will be distributed more in the body water spaces. When the number of available binding sites is reduced by a second drug, it will appear as if there has been an increase in overall drug concentration.

Although drugs are predominantly bound to albumin, the amount taken up by erythro-cytes must not be neglected, as can be seen in Fig. 10.22.

More directly, the effect of protein binding on antibiotic action is worth considering.

Sulfafurazole

87% Sulfadazine

Figure 10.22 Distribution of three sulfonamides and p-aminobenzoic acid between albumin, plasma water and erythrocytes in humans. Log P values for octanol/water are: sulfafurazole 1.15; sulfamethoxazole 0.88; and sulfadiazine 0.13. Binding to albumin correlates with lipophilicity.

Reproduced from K. Berneis and W. Boguth, Chemotherapy, 22, 390 (1976).

Penicillins and cephalosporins bind reversibly to albumin. Only the free antibiotic has antibacterial activity. Oxacillin in serum at a concentration of 100 ^g cm 3 exhibits an antibacterial effect similar to that of 10 ^g cm 3 of the drug in water. A high degree of serum protein binding may nullify the apparent advantage of higher serum levels of some agents (Table 10.10). An increase in the lipo-philicity of penicillins results in decreased activity, although one normally expects that this should enhance penetration of bacterial cell walls and also absorption. The hydro-phobic binding of penicillins in serum proteins reduces their potency in vivo, however, by decreasing their effective concentration. Thus, comparisons between antibiotics are best made with activity-time plots and not serum concentration profiles, as the free levels often differ from the total antibiotic levels (see, for example, values for cloxacillin and benxylpenicillin in Table 10.10).

The second important consequence of protein binding is related to the fact that only free drug is able to cross the pores of the capillary endothelium. At equilibrium, levels of free drug on both sides of the capillary wall are equal. Albumin levels in most sites are considerably less than those in serum, so there is

Sulfamethoxazole

Sulfamethoxazole p-Aminobenzoic acid 9.7%-

p-Aminobenzoic acid 9.7%-

Table 10.10 Protein binding and other characteristics of some penicillins and cephalosporins0

Antibiotic

Log Pb

Serum protein

Serum concentration

Peak serum

0 0

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