Drug absorption techniques

JT. Doluisio, NF Billups, LW Dittert, ET Sugita, JV Swintosky. Drug absorption. I. An in situ rat gut technique yielding realistic absorption rates. J Pharm Sci 58 1196-1200, 1969. 

While in vivo studies assess absorption rates as process-lumped time constants from blood level versus time data, these rate parameters encompass the kinetics of dosage-form release, GI transit, metabolism, and membrane permeation. The use of isolated tissue and cellular preparations to screen for drug absorption potential and to evaluate absorption rate limits at the tissue and cellular levels has been expanded by the pharmaceutical industry over the past several years. For more detail in this regard, the reader is referred to an article by Stewart et al. [68] for references on these preparations and for additional details on the various experimental techniques outlined below. 

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. 

M. J., Biopartitioning micellar chromatography an in vitro technique for predicting human drug absorption, J. Chromatogr. B 2001, 753, 225-236. 

A review of GI transit and oral drug absorption can be organized in many ways, but a logical sequence is to start at the top and work down. In this review, techniques to study buccal and rectal delivery will not be covered, but a detailed description of these is available in a recent book (1). 

Originating from the neurosciences, the microdialysis technique has been used since several years to monitor drug absorption and disposition or the levels of endogenous substances in the extracellular space of different organs and fluids, such as bone, lung, liver, brain, and blood. The method has evolved from its use in different animal species to the human microdialysis during the late 80s [35],... 

The advantages of the in situ techniques include an intact blood supply multiple samples may be taken, thus enabling kinetic studies to be performed. A fundamental point regarding the in situ intestinal perfusion method is that the rat model has been demonstrated to correlate with in vivo human data [46 19], Amidon et al. [36] have demonstrated that it can be used to predict absorption for both passive and carrier-mediated substrates. However, the intestinal luminal concentrations used in rat experiments should reflect adequately scaled and clinically relevant concentrations to ensure appropriate permeability determinations [50], There are limitations of the in situ rat perfusion models. The assumption involved in derivation of these models that all drug passes into portal vein, that is drug disappearance reflects drug absorption, may not be valid in some circumstances as discussed below. 

Direct determination of portal blood flow rate is difficult and would generally require placement of an electronic flow probe in each animal. However the technique proposed by Hoffman et al. utilised tritiated water as an absorption probe (i.e. internal standard) [89], By dosing and sampling drug/ absorption probe concurrently, factors such as variable portal blood flow rate are normalised between experiments. 

Lennernas s group at Uppsala has performed extensive studies to confirm the validity of this in vivo experimental set-up at assessing the rate and the extent of drug absorption. Recovery of PEG 4000 (a non-absorbable marker) is more than 95%, which indicates that the absorption barrier is intact. In addition, maintenance of functional viability of the mucosa during perfusion has been demonstrated by the rapid transmucosal transport of D-glucose and L-leucine. Estimation of absorption half-lives from the measured Pefr agree well with half-lives derived from oral dose studies in humans (i.e. physiologically realistic half-lives). Human Peff estimates are well correlated with the fraction absorbed in humans, and served as the basis for BCS development, and hence the technique is ultimately the benchmark by which other in situ intestinal perfusion techniques are compared. The model has been extensively used to... 

In situ techniques suffer the disadvantage that the animal is anaesthetised for the duration of the experiment. Surgery and anaesthesia change several physiological factors that can alter drug absorption characteristics. Anderson et al. [117] found the ABL thickness in laparotomised rats to be higher than in conscious non-laparotomised rats. Yuasa et al. [118] reported that... 

Doluisio JT, Billups NF, Dittert LW, Sugita ET and Swintosky JV (1969) Drug Absorption. An In Situ Rat Gut Technique Yielding Realistic Absorption Rates. J Pharm Sci 58 pp 1196-1200. 

Schurgers N, Bijdendijk J, Tukker JJ and Crommelin DJ (1986) Comparison of Four Experimental Techniques for Studying Drug Absorption Kinetics in the Anaesthetized Rat in Situ. J Pharm Sci 75 pp 117-119. 

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