Subject(s)
Bacterial Infections/drug therapy , Enzyme Inhibitors/pharmacokinetics , Fever/metabolism , Trimethoprim/analogs & derivatives , Animals , Bacterial Infections/metabolism , Disease Models, Animal , Enzyme Inhibitors/therapeutic use , Rectum/metabolism , Sheep , Time Factors , Trimethoprim/pharmacokinetics , Trimethoprim/therapeutic useABSTRACT
A simple, highly sensitive radioassay was developed for the activity of a newly discovered inhibitor of dihydrofolate reductase (DHFR), aditoprim. The procedure is based on the inhibition of binding of [3H]-methotrexate ([3H]MTX) with bacterial dihydrofolate reductase by the antifolate, aditoprim. The analytic sensitivity using this binding inhibition method was less than 5 ng in plasma. The procedure developed requires no extraction of the drug from the plasma. The variation of simultaneous duplicate determinations was 6.3 per cent, whereas the variability of plasma samples assayed on different days was less than 11 per cent. The assay developed was applied to study the pharmacokinetics of aditoprim in the goat. In comparison with trimethoprim (TMP), the new inhibitor of DHFR, aditoprim, had a longer half-life and a larger volume of distribution, suggesting enhanced and prolonged antibacterial activity of aditoprim over TMP.
Subject(s)
Folic Acid Antagonists , Trimethoprim/analogs & derivatives , Animals , Goats , Half-Life , Models, Biological , Radioligand Assay , Sheep , Trimethoprim/blood , Trimethoprim/pharmacokineticsABSTRACT
Two patients with osteogenic sarcoma were treated with high-dose methotrexate (MTX) followed by leucovorin 'rescue'. Profiles of MTX clearance from plasma and erythrocytes were obtained. Clearance of the drug from plasma during the first 36 hours appears to be biphasic with the first phase of elimination of the drug being appreciably more rapid than the second phase. The drug had also incorporated into the bone marrow precursor cells and reappeared after a few days in the circulating mature erythrocytes which may later serve as a slow-changing compartment for MTX. Nonspecific binding of the drug to plasma proteins may have been one of the causes of delayed clearance of plasma MTX observed in one of the patients. However, delayed clearance does not appear to correlate with the severity of clinical toxicity which was found to be more pronounced in a patient with a better clearance of the drug. Our results support the more recent concept that enhanced clinical toxicity may not be predictable by monitoring plasma MTX alone.
