Nonlinear pharmacokinetics: clinical Implications.

摘要: Nonlinear pharmacokinetics (in other words, time or dose dependences in pharmacokinetic parameters) can arise from factors associated with absorption, first-pass metabolism, binding, excretion and biotransformation. Nonlinearities absorption bioavailability cause increases drug concentrations that are disproportionately high low relative to the change dose. One of more important sources nonlinearity is partial saturation presystemic metabolism exhibited by such drugs as verapamil, propranolol hydralazine. In cases, circulating sensitive not only size but also rate absorption: slower may decrease overall systemic availability. The binding plasma constituents, blood cells extravascular tissue exhibit concentration dependence. This parameters based on total serum be concentration-dependent. Often, these free appear linear. An consideration regard concentration-dependent difficulty relating a usual therapeutic range if better indicator effect. Measurement needed particularly intersubject variability high. example this behaviour valproic acid. Partial elimination pathways result well known typical Michaelis-Menten pharmacokinetics. Small changes dosing make much larger differences steady-state concentration. achieve given fraction becomes longer approaches maximum rate. Alcohol phenytoin examples behaviour. sensitivity cumulation both influenced magnitude parallel first-order pathways: even pathway 1 2% clearance (which occurs at very concentration) an determinant when Theophylline salicylate have significant saturable pathways. Autoinduction causes increase long term administration. some dosage adjustment must made compensate for increase, possibility degree induction dose- kept mind. Carbamazepine major autoinduction. It fortunate few many hundreds use nonlinear leads clinical implications.(ABSTRACT TRUNCATED AT 400 WORDS)