Oral drug absorption kinetics

The CAT model considers passive absorption, saturable absorption, degradation, and transit in the human small intestine. However, the absorption and degradation kinetics are the only model parameters that need to be determined to estimate the fraction of dose absorbed and to simulate intestinal absorption kinetics. Degradation kinetics may be determined in vitro and absorption parameters can also be determined using human intestinal perfusion techniques [85] therefore, it may be feasible to predict intestinal absorption kinetics based on in vitro degradation and in vivo perfusion data. Nevertheless, considering the complexity of oral drug absorption, such a prediction is only an approximation. 

Oral drug absorption is often described as a first-order mechanism, and through compartmental modeling, oral absorption is represented by the first-order absorption rate constant, ka (per time unit). Although it is not used in the current example, inclusion of lag time may be needed to better describe absorption processes. The kinetics of drug amount in the plasma following a first-order absorption process is described by a system of differential equations, as follows ... 

To predict oral plasma concentration-time profiles, the rate of drug absorption (Eq. (53)) needs to be related to intravenous kinetics. For example, in the case of the one-compartment model with first-order elimination, the rate of plasma concentration change is estimated as... 

Tucker IG (1988) A method to study the kinetics of oral mucosal drug absorption from solutions. J Pharm Pharmacol 40 679-683... 

KINETICS OF DRUG ABSORPTION AFTER ORAL ADMINISTRATION... 

FIGURE 9.12 Kinetics of drug absorption and elimination as viewed by the plasma concentration of an orally administered drug with time. 

The kinetics of 5-fluorouracil and its metabolites are essentially nonlinear. Therefore it is extremely difficult to build models that would correctly describe the cascade of nonlinear transformations that are observed, starting from drug absorption to its transformation into the active moiety. More recently, capecit-abine has been commercialized. It is a fluor-pyrimidine carbamate available for oral administration. Concentrations of 5-fluorouracil in some tumors are higher than those in the adjacent healthy tissues. The tumor preferential activation of capecitabine to 5-fluorouracil is explained by tissue differences in the activity of cytidine deaminase and thymidine phos-phorylase. It is interesting to note that the last of the three metabolic steps leading to 5-fluorouracil is the formation of 5 -deoxy-5-fluori-dine. Capecitabine is thus a pro-prodrug (176-178). 

The partition theorem can also be applied to the disintegration and absorption kinetics of an oral tablet to determine the MRT of the drug in the various kinetic spaces in the drug delivery sequence (Figure 16.5A). The residence of the drug can be partitioned into four kinetic spaces (Figure 16.5) ... 

Lee, K.W.Y. Nguyen, T.H. Hanley, T. Boyd, B.J. Nanostructure of liquid crystalline matrix determines in vitro sustained release and in vivo oral absorption kinetics for hydrophilic model drugs. Int. J. Pharm. 2009, 365 (1-2), 190-199. 

The aqueous solubility of indinavir is pH dependent, with increased solubility at acidic pH. During development, the compound was initially used in the free base monohydrate form and its absorption kinetics was tested in rats and dogs in two separate formulations of (i) 0.5% methocel suspension and (ii) 0.05 M citric acid solution, for an oral dose of 10 mg kg In rats, indinavir attained a C ax value of 0.56 pM in 15 min in the methocel formulation, almost similar to that in citric acid (C ax 0-44 pM in 35 min). In dogs, there were more prominent differences in the two formulations. The C ax value in methocel suspension was 3.72 pM in 25 min as opposed to 11.4 pM in 30 min in the citric acid solution. It was also observed that the bioavailability of indinavir in both rats and dogs was quite similar ( 16%) when administered as a 10 mg kg dose in methocel suspension. However, in 0.05 M citric acid solution, the bioavailability of the drug in dogs was approximately 33% higher than that in rats. 

Prasad et al. [126] developed and used a sensitive and specific spectropho tome trie method for the estimation of primaquine to study the plasma kinetics of primaquine in Rhesus monkeys. It was observed that the drug completely disappeared from the plasma in 24 h after a single oral dose. Its concentration in the plasma reached a peak at 2 h of administration. The mean absorption and elimination half-lives were 0.36 0.08 and 3.44 0.37 h, respectively. 

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