Oral absorption process

Figures 2.1 and 2.2 represent the basic model that will be used to discuss the literature related to the measurement of the physicochemical parameters and the interpretation of their role in the oral absorption process [19,20,23,45-61].

Although, the pH-partition hypothesis has not been found to be universally applicable, it has resulted in the recognition of the important contribution of GI pH to permeability and to the dissolution rate of solid dosage forms. This theory does not consider the solubility of the drug, which is a critical physicochemical parameter in the oral absorption process. Dressman et al. [34] developed an absorption potential concept that takes the two parameters into account. The absorption potential is defined as... 

In general, it is assumed that the oral absorption process follows Lrst-order kinetics. This assumption appears to be valid for majority of the drugs. The Lrst-order process can also satisfactorily describe the oral absorption process of some drugs with very poor water solubility. Sometimes, the inclusion of the absorption time lag may appear to be needed to account for the lag time for the dissolution of the drug substance from the dosage form into the aqueous media in the Gl tract. 

The oral absorption process requires two steps for completion. The drug must first cross the epithelial layer of the gastrointestinal tract. Because of the increased... 

Absorption. No studies were located regarding the mechanism of absorption in humans or animals after inhalation, oral, or dermal exposure to diisopropyl methylphosphonate. Both facilitated transport and diffusion through the lipophilic portions of the membrane could be involved in absorption processes. No data were found regarding lipid solubility or partition coefficients. 

Fig. 10 Urinary excretion of riboflavin (A, B) and ascorbic acid (C, D) in humans as a function of oral dose. Graphs A and C illustrate the nonlinear dependence of absorption on dose, which is suggestive of a saturable specialized absorption process. Graphs B and D represent an alternative graph of the same data and illustrate the reduced absorption efficiency as the dose increases. (Graphs A and C based on data in Ref. 39 and graphs B and D based on data in Ref. 40.)...

One excellent study [151] employed intravenous and oral dosing at each of several times postsurgery (1-2 weeks, 6 and 12 months). This design permits valid conclusions about the absorption process. There was a significant reduction after surgery in ampicillin absorption but no change in propylthiouracil absorption. 

The most common extravascular route is oral. When a solution or a rapidly dissolving solid dosage form is given orally, the absorption process often obeys first-order kinetics. In these cases, absorption can be characterized by evaluating the absorption rate constant, ka, using plasma concentration versus time data. 

Equation (35) describes the line in Fig. 10, which is a semilog plot of Cp versus time for an orally administered drug absorbed by a first-order process. The plot begins as a rising curve and becomes a straight line with a negative slope after 6 hours. This behavior is the result of the biexponential nature of Eq. (35). Up to 6 hours, both the absorption process [exp(—kat) and the elimination process [exp( keil)] influence the plasma concentration. After 6 hours, only the elimination process influences the plasma concentration. 

Another new development has been the application of oral absorption promoters. These materials are designed to enhance the oral bioavailability of many compounds and improve variable absorption. However, many of these compounds are hydrophobic in nature and cause difficulty during tableting itself. The challenge for formulators is to arrive at clever solutions to the process problems while retaining material performance. 

An important part of the optimization process of potential leads to candidates suitable for clinical trials is the detailed study of the absorption, distribution, metabolism and excretion (ADME) characteristics of the most promising compounds. Experience has learned that physico-chemical properties play a key role in drug metabolism and pharmacokinetics (DMPK) [1-3]. As an example, physicochemical properties relevant to oral absorption are described in Fig. 1.1. It is important to note that these properties are not independent, but closely related to each other. 

The barriers confronting oral delivery of a drug molecule are summarized in Fig. 13.1. During the absorption process, the drug must cross the enterocyte cell apical... 

In spite of its limitations, the ACAT model combined with modeling of saturable processes has become a powerful tool in the study of oral absorption and pharmacokinetics. To our knowledge, it is the only tool that can translate in vitro data from early drug discovery experiments all the way to plasma concentration profiles and nonlinear dose-relationship predictions. As more experimental data become available, we believe that the model will become more comprehensive and its predictive capabilities will be further enhanced. 

In other studies, bisphosphonate-pamidronate or alendronate were linked to the terminal carboxylic acid of the stabilized dipeptide Pro-Phe to improve the bioavailability of bisphosphonates by hPepTl-mediated absorption. In-situ single-pass perfused rat intestine studies revealed competitive inhibition of transport by Pro-Phe, suggesting carrier-mediated transport. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration to rats. The authors suggested that oral bioavailability of bisphosphonates may be improved by PepTl-mediated absorption when administered as peptidyl prodrugs [53]. Future mechanistic studies may prove if hPepTl is involved in the absorption process. 

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