DOSE-DEPENDENCE OF DRUG PLASMA LEVEL DECLINE IN DOGS

¹ New York University Research Service, Goldwater Memorial Hospital, Welfare Island, New York
² New York University Research Service, Goldwater Memorial Hospital, Welfare Island, New York, New York

It has been found that for several drugs the rate of disappearance from plasma is dependent on the dose. For example, the rate of phenylbutazone metabolism is faster after low than after relatively high doses. Similar results have been observed with biscoumacetate, probenecid, diphenyihydantoin and two analogs of phenylbutazone. In order to rule out the interference of metabolites in the analyses, the determinations have been made with specific methods, as confirmed by such techniques as quantitative thin-layer chromatography. Alterations in binding to plasma proteins due to changes in plasma concentration cannot alone explain the dose-dependent decline in plasma levels, nor can urinary excretion of unchanged drug, since this route of elimination is not significant for the compounds in question. The effect of dose on plasma level decline rate has been interpreted as a special case of inhibition, the self-inhibition of metabolism of a drug. Additional evidence for this hypothesis was obtained from experiments with the microsomal inhibitor SKF 525A and with known stimulators of microsomal drug-metabolizing enzymes. The significance of the phenomenon in the interpretation of the effect of pretreatment with other drugs on plasma level decline is discussed.