Abstract
Most drugs display their therapeutic activity on specific places in the human body and should reach the systemic circulation in order to be transported towards the site of action. Irrespective of the route of administration the same sequence of steps are of relevance for the exposure to a drug: release
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from the dosage form (dissolution), absorption into the blood (permeation through a biological membrane) and finally removal from the body (metabolism and elimination).
The first part of this thesis focusses on the physicochemical properties of drugs. Chapter 2 evaluates the physicochemical properties of drugs required to achieve appropriate absorption upon several routes of administration (oral, transdermal, buccal/sublingual, nasal and vaginal). It appeared that the physicochemical properties required for absorption do not vary to a large extent through the different routes of administration and the solubility was identified as one of the most critical parameters emphasizing the importance of the formulation.
In the second study the physicochemical properties and gastrointestinal permeability of steroids were evaluated in relation to absorption (chapter 3). Of the calculated physicochemical properties (molecular weight, number of hydrogen bond donor and acceptor sites, number of rotatable bonds, Polar Surface Area and ClogP) ClogP was the most discriminative descriptor. The measured apparent permeability coefficients (Papp, Caco-2 cells) showed that all steroids were well transported over the cell monolayers.
In the next study the gastrointestinal absorption and P-glycoprotein (Pgp) efflux transport of heterocyclic drugs was investigated (chapter 4). Since Pgp is expressed at the Blood Brain Barrier as well, it can be expected that CNS penetration will be impaired if a drug is a Pgp substrate. The transport data showed that most drugs tested display a high permeability over the cells and that the Pgp efflux transporter was expressed. However, no correlation could be found between brain penetration in rats and the Pgp efflux ratio as measured with the Caco-2 cells.
An alternative route for intestinal absorption is lymphatic uptake. The major advantages are found in the fact that first pass metabolism is circumvented and the possibility to deliver very hydrophobic drugs to the systemic circulation. It was investigated whether it is feasible to predict the potential of drugs for lymphatic absorption (chapter 5). It was shown that partition coefficients (octanol/water, ex vivo dog lymph or Intralipd) offer the possibility to assess the potential for lymphatic transport of drugs. The Caco-2 transport data showed that Caco-2 cells are not suitable for assessing the potential of drugs for lymphatic absorption.
In the second study involving lymphatic drug delivery, the contribution of lymphatic absorption of testosterone undecanoate (TU), a very hydrophobic drug, to the systemic exposure of testosterone (T) was determined (chapter 6). In a thoracic lymph duct-cannulated dog model, the oral bioavailability and lymphatic transport of TU after postprandial administration was determined. These data demonstrate that intestinal lymphatic transport of TU is responsible for the systemic exposure of T by avoiding the extensive first-pass effect.
Finally, a novel methodology was proposed to evaluate the possibility for waiving bioequivalence studies on the basis of standard human pharmacokinetic data (chapter 7).
It was shown that if a drug exhibits dose linear pharmacokinetics and a sufficiently fast dissolution profile, it can be concluded that this drug appears to pose no problem with respect to absorption. Provided that the dissolution profiles of the different formulations are equal bioequivalence can be guaranteed.
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