The simplest model for ocular pharmacokinetics is shown in Figure 1 (5). It is well known that for most drugs the true absorption rate constant is much smaller than the elimination rate constant. This will normally give rise to a flip-flop model. However, when the parallel elimination pathway is introduced (Fig. 2) (5), the apparent absorption rate constant is defined as:
Apparent kabs = kabs + kloss>pp
Thus, the model is not a flip-flop model and drug concentration can be described as
where F is the fraction of dose absorbed, D is the dose, k and K are absorption and elimination rate constants, respectively, and Vd is the apparent volume of distribution. Obviously, K = kelim, k = kabs + kloss pp.
For many drugs, kloss; pp is of the order of 0.5-0.7 min-1, being several orders of magnitude larger than kabs, which is typically of the order of 0.001 min-1. As a result, the peak time, which is controlled by klosspp and kabs, is similar (20-40 min) for a wide range of compounds since kloss pp, which is mainly due to drainage, induced lacrimination, etc., predominates over kabs in controlling the peak time.
In order to improve the bioavailability (F = kabs/[kabs + kloss pp]) significantly, it is essential to increase kabs by one or two order of magnitudes or reduce kloss pp to a similar extent.
Several approaches have attempted to reduce the magnitude of kloss pp. However, it has its limit. Keister et al. (6) showed that reducing the dose volume from 25 mL to zero brings only a fourfold improvement in bioavailability for a poorly permeable compound. However, it is practically impos-
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