Drug Input Rate from the GI-Tract. Michaelis-Menten Kinetics and the Bioavailability of Slow-Release Verapamil and Nifedipine

Summary

• 1. This paper presents evidence from studies with slow release verapamil and nifedipine for Michaelis-Menten metabolism during first pass through the liver. Drug input rate from the Gl-tract after an oral dose appears to be a determinant of biovailability. Highest oral bioavailabilities are observed with standard release formulations at high dosage. The bioavailability of slow release formulations with a zero order release kinetic is lower than standard release formulations and related to the dissolution rate in vitro.

• 2. The presence of non-linear absorption kinetics offers a further explanation for the considerable inter-patient variability in AUG since the ability of drug to cross the liver is a function of the concentrations attained in portal blood which will be dependent on dissolution conditions prevailing in the GI-tract.

• 3. Depending on the choice of the dose and dosage interval of the conventional release formulation used for comparison, and as a consequence of Michaelis- Menten first pass metabolism, it is possible to obtain relative bioavailability data showing superiority, equivalence, or biovailability loss with the slow release form. This may explain the discrepancies in bioavailability data for slow release drugs reported in the literature.

• 4. ‘True’ estimates of relative bioavailability of a slow release formulation can only be achieved if:

  • a) Steady state conditions are present.

  • b) The dose and dosage interval of the slow and conventional release formulation are the same.

• 5. Since a slower dissolution rate is ‘ipso facto’ associated with a lower bioavailability, slow release formulations of verapamil and nifedipine cannot be classified as being ‘inferior’ or of poorer quality on the basis of bioavailability alone.