The pharmacokinetics of antipyrine have been reassessed to establish more firmly the relative utility of antipyrine half-life and disposition rate constant as indices of antipyrine metabolic clearance rate. Pharmacokinetic analyses were performed from previously published studies on healthy volunteers. In addition healthy, non-smoking, non-obese male volunteers (109 from Hershey, PA and 31 from Bristol, UK) and groups of patients with various forms of liver disease were investigated. For any given apparent volume of distribution, the relationship of clearance and disposition rate constant is linear, whereas the relationship between clearance and half-life is hyperbolic. However, over the range of values commonly observed in healthy volunteers for antipyrine clearance, the relationship between antipyrine clearance and half-life approximates linearity. Over the entire range of values for antipyrine clearance, linearity emerges when either I/t1/2 or the disposition rate constant is plotted against clearance. The common practice of correcting clearance and volume of distribution for bodyweight was evaluated as a way to normalise the data. The correlation of clearance with bodyweight was low; weight correction did not normalise the data. Although there was no biologically relevant reason for weight adjustment, it was noted that the relationship between clearance/bodyweight and disposition rate constant or half-life gave the highest correlation coefficient values obtained in both this study and the literature. This results from the fact that distribution volume was positively correlated with bodyweight and weight correction did indeed normalise the data. Thus, the term clearance/bodyweight is in fact a hybrid, volume-corrected parameter, thereby accounting for the good (but not perfect) relationship. We evaluated the reliability of changes in disposition rate constant or half-life to quantify altered elimination in chronic liver disease and phenobarbitone-treated subjects. Because volume of distribution was unchanged, changes in disposition rate constant (β) accurately reflected altered clearance. To use half-life as an index of changes in clearance produced by any of numerous modalities, such as chronic liver disease or drug administration, the proper equation is line equation 264-1, and not line equation 264-2 The reason for this is that half-life is inversely related to clearance. Furthermore, when the commonly used relationship line equation 264-3 was employed, impairment in drug elimination was overestimated and enzyme induction underestimated. Aging reduced both antipyrine volume of distribution and clearance so that changes in antipyrine half-life underestimated effects of age on antipyrine elimination.
All Science Journal Classification (ASJC) codes
- Pharmacology (medical)