The effect of pyrogen on the in vivo metabolism and initial kinetics of chloroquine in rats

Abstract

Abstract The possible contribution of hepatic metabolism impairment, caused by pyrogen, to the increased toxicity and altered pharmacokinetics of chloroquine in rats was investigated. The ratio of unchanged chloroquine (CQ) to total quinolines (TQ) was determined in the 24-h urine collection, the plasma and the liver. Pretreatment with massive doses of E. coli lipopolysaccharide pyrogen did not produce any significant change in the ratio of CQ/TQ in the urine, liver or plasma between control and pyrogen-treated rats. This finding occurred in spite of a pronounced initial behavioural effect of the pyrogen on the rats. The ratio of CQ/TQ was also preserved in the 7th day 24-h urine collection from a control and a pyrogentreated rat although the total urinary excretion of TQ had decreased by about 99·5% of the first 24-h collection. Analysis of the pharmacokinetic parameters from plasma levels in the first 24 h showed significant alterations in the apparent volume of distribution (AVD), the half-life (T 1/2) and the rate of decay constant (K) of the drug in pyrogen-treated rats. These findings were interpreted to indicate that chloroquine metabolism in vivo, which occurs mainly via a dealkylation process, may not be readily deranged by pyrogen. The changes in the pharmacokinetic parameters are discussed in relation to the known haemodynamic changes that occur in the febrile state.