Injection site residues, pharmacokinetic

Injection Site Residues and Flip-Flop Pharmacokinetics... 

Pharmacokinetic studies (59) in cattle treated with the recommended dosage showed that the drug was well dispersed from the injection site, with less than 1% of the dose remaining at 21 day withdrawal. By 14 days, 87% of the dose was excreted via the bile and feces whereas less than 1% was eliminated via urine. Mean plasma half-life was found to be 6.2 days for the parent compound and 5.9 days for total drug-related residues. 

Apart from the pathophysiological condition of the animal, the mode of drug application may also significantly influence the pharmacokinetic profile of a drug (48, 49). For example, drug residues may persist at the injection site for prolonged periods of time (2). In a study in which various sulfonamides and trimethoprim were injected intramuscularly into swine, detectable residues were found at most sites 6 days after the injection, and with the sulfonamides at 30 days in almost half of the animals (50). Other drugs such as dihydrostreptomycin persist for up to 60 days, while positive residues of chloramphenicol are found at 7 days postinjection. Sodium and procaine penicillin, neomycin, tylosin, and oxytetracycline residues have also been determined at 24 h or more postinjection (51). 

Residues at the site of injection present specific problems. The persistence of residues at intramuscular injection sites may be due in part to the irritant response produced in the muscle. Chloramphenicol, tylosin, penicillins, dihydrostreptomycin and oxytetracycline have been shown to produce local irritation at the site of injection leading to residues persistence and this may be exacerbated by the solvent used (47-49) with one oxytetracycline product which produced little irritation, residues did not persist (49). Large variations in pharmacokinetic behaviour were noted in addition to the persistence at the injection site and in particular with oxytetracycline, bioavailability was reduced. These studies demonstrate the usefulness of pharmacokinetic data when studying specific routes of administration, and in particular they demonstrate the need to take into account other biological phenomena when attributing withdrawal periods, in this case, irritation at the injection site. The new draft EC Guideline requires that injection sites are examined in residues studies with injectable products and in the case of persistence at the site, then the withdrawal period will be based on this. 

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