Input rate-dependent stereoselective pharmacokinetics: enantiomeric oral bioavailability and blood concentration ratios after constant oral input.

A pharmacokinetic model and relevant equations were used to simulate the blood concentration ratio (Cratio) and oral bioavailability ratio (Fratio) of the two enantiomers of model racemic drugs after different oral input rates. The simulations were carried out for six metabolically eliminated racemic drugs with regard to differences between the two enantiomers in their metabolic maximum velocity (Vmax) and/or Michaelis-Menten constant (Km). Both Cratio and Fratio values were dependent on the oral input rate of the drugs, with the maximum sensitivity observed for input rates close to the Vmax of the enantiomers. However, at input rates substantially lower or higher than Vmax, the dependence of ratios to input rate was minimal. The profile of dependence of Cratio and Fratio on the input rate differed for the various modeled drugs and, in one case, input rate alteration lead to a reversal in the stereoselectivity of the ratios. Relevance of these findings with regard to alterations in the dose and/or formulation of racemic drugs is discussed.