Gastrointestinal fluid

Krondahl, E., Orzechowski, A., Ekstrom, G., Lennernas, H., Rat jejunal permeability and metabolism of mu-selective tetrapeptides in gastrointestinal fluids from humans and rats, Pharm. Res. 1997, 34, 1780-1785. 

Fig. 15.1. Factors limiting oral drug absorption. Dissolution and the aqueous drug solubility in the gastrointestinal fluids are two of the properties influencing oral drug absorption. When the drug is in solution, it can be subjected to chemical degradation and complex binding with components of the gastrointestinal fluids and/or be metabolised by...

Let us conclude this section by proposing that provided that the drug is sufficiently soluble in the gastrointestinal fluids, the complex process of intestinal drug absorption can often be satisfactorily described by focusing on passive transport across the cell membrane, and that the development of models that predict passive transcellular permeability is particularly important. Such models are the focus of the remaining part of this chapter. 

Limited oral drug bioavailability may be explained by poor membrane permeability, low aqueous solubility in gastrointestinal fluids, or extensive first-pass metabolism in the gastrointestinal tract or liver. Successful lipophilic prodrugs... 

Rate of dissolution in gastrointestinal fluids. Chemicals that are inadequately dissolved in gastric contents may be inadequately absorbed. 

Lomstein Pedersen B, Mullertz A, Brondstedt H, Gjelstrup Kristensen H (2000) A comparison of the solubility of danazol in human and simulated gastrointestinal fluids. Pharm. Res. 17 891-894. 

E. Krondahl, A. Orzechowski, G. Ekstrom, H. Lennemas, Rat Jejunal Permeability and Metabolism of /i-Selective Tetrapeptides in Gastrointestinal Fluids from Humans and Rats , Pharm. Res. 1997, 14, 1780-1785. 

Solubility is highly influenced by the solid-state form (e.g., crystalline or amorphous) of the drug. Rigorous solubility studies using the final solid form (i.e., salt form or crystal form) as a function of temperature (i.e., 25 and 37°C) and pH (range 1 to 7.5) are conducted during preformulation. Solubility in nonaqueous solvents is also screened. Solubility in simulated gastrointestinal fluids is also important. 

Water-soluble substances will readily dissolve into the gastrointestinal fluids however, absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. If the molecular weigjit is low (less than 200), the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. 

Severe hypotension can occur after initial doses of any ACE inhibitor in patients who are hypovolemic as a result of diuretics, salt restriction, or gastrointestinal fluid loss. Other adverse effects common to all ACE inhibitors include acute renal failure (particularly in patients with bilateral renal artery stenosis or stenosis of the renal artery of a solitary kidney), hyperkalemia, dry cough sometimes accompanied by wheezing, and angioedema. Hyperkalemia is more likely to occur in patients with renal insufficiency or diabetes. Bradykinin and substance P seem to be responsible for the cough and angioedema seen with ACE inhibition. 

Most oral preparations are solid dosage forms that need to be dissolved before they can be absorbed. The inert ingredients of such dosage forms can have a profound effect on the dissolution of the active ingredient and thereby control its rate of absorption. In addition, the drug may be unstable in the gastrointestinal fluids, as in the case of penicillin G, or metabolized. 

The rate and extent of absorption of drug Y will be a function of its solubility, intestinal permeability, and stability in the gastrointestinal fluids and dissolution rate. Differences in the absorption of two phannaceutically equivalent products should then primarily be a function of their in vivo dissolution rate differences, assuming the excipients used do not alter bioavailability [38]. Therefore, the key question here is Does an in vitro dissolution test emulate in vivo drug dissolution ... 

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