Tissue fluid, free drug level

PAS is readily absorbed from the GI tract and is widely distributed throughout body fluids except cerebrospinal fluid. It penetrates tissues and reaches high concentrations in the tuberculous cavities and caseous tissue. Peak plasma levels are reached within 1 to 2 hours of drug administration, and the drug has a half-life of about an hour. PAS is primarily metabolized by hepatic acetylation. When combined with isoniazid, PAS can function as an alternative substrate and block hepatic acetylation of isoniazid, thereby increasing free isoniazid levels. Both the acetylated and unaltered drug are rapidly excreted in the urine. The concentration of PAS in urine is high and may result in crystalluria. 

The level of free dmg in semm is important in determining the amount of dmg which reaches tissue spaces. The total concentration of a drug in tissue fluid can be predicted from the semm concentration, the extent of semm protein binding, and the protein binding in the tissue fluid. Equation (10.18) has been shown to be highly predictive under equilibrium conditions ... 

In a great many cases the level of free drug in the tissue fluids eventually becomes the same as that in the plasma. This relationship is convenient because the plasma is more accessible for analysis. Among examples investigated are the anti-bacterial sulfonamide, sulfadoxine ( Fanasil ) in the intraperitoneal cavity of rats after oral injection (McQueen, 1968), also various penicillins in lymph of dogs. The literature of this correlation has been reviewed by Robinson (1966). 

The usual dosage of chloramphenicol is 50-100 mg/kg/d. After oral administration, crystalline chloramphenicol is rapidly and completely absorbed. A 1-g oral dose produces blood levels between 10 and 15 mcg/mL. Chloramphenicol palmitate is a prodrug that is hydrolyzed in the intestine to yield free chloramphenicol. The parenteral formulation is a prodrug, chloramphenicol succinate, which hydrolyzes to yield free chloramphenicol, giving blood levels somewhat lower than those achieved with orally administered drug. Chloramphenicol is widely distributed to virtually all tissues and body fluids, including the central nervous system and cerebrospinal fluid, such that the concentration of chloramphenicol in brain tissue may be equal to that in serum. The drug penetrates cell membranes readily. 

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