Bioavailability drug absorption

Chan LM, Lowes S, Hirst BH (2004) The ABCs of drug transport in intestine and liver efflux proteins limiting drug absorption and bioavailability. Eur J Pharm Sci 21 25—51... 

A special case for reduced bioavailabilty results from first-pass extraction that sometimes might be subjected to saturable Michaelis-Menten absorption kinetics. The lower the hepatic drug clearance is (Clhep) in relation to liver blood flow (Ql), or the faster the drug absorption rate constant (Ka), and the higher the dose (D) are, the more bioavailable is the drug (F). 

Van de Waterbeemd, H. Physicochemical approaches to drug absorption. In Drug Bioavailability Estimation of Solubility, Permeability, Absorption and Eioavailability (Methods and Principles in Medicinal Chemistry), Van der Waterbeemd, H., Lennernas, H Artursson, P. (eds.), Wiley-VCH, Weinheim, 2003, pp. 1-20. 

In conclusion, it should be apparent from this discussion of the absorption mechanisms that, although the major features influencing drug absorption are well known, implementation of a coherent delivery strategy is highly specific for any compound, and many variables need to be adjusted for their significant influence on absorption and more importantly, on bioavailability. In addition, from the suggestion of the role of... 

Drug absorption is highly variable in neonates and infants [21,22]. Older children appear to have absorption patterns similar to adults unless chronic illness or surgical procedures alter absorption. Differences in bile excretion, bowel length, and surface area probably contribute to the reduced bioavailability of cyclosporine seen in pediatric liver transplant patients [22a]. Impaired absorption has also been observed in severely malnourished children [22b]. A rapid GI transit time may contribute to the malabsorption of carbamazepine tablets, which has been reported in a child [23]. Selection of a more readily available bioavailable dosage form, such as chewable tablets or liquids, should be promoted for pediatric patients. 

Application of ultra-high-throughput in silico estimation of biopharmaceutical properties to the generation of rule-based computational alerts has the potential to improve compound selection to those drug candidates that are likely to prove less troublesome in their development. The extension of purely in silico methods to the realm of mechanistic simulation further enhances our ability to predict the impact of physiological and biochemical process on drug absorption and bioavailability. 

Oral bioavailability of a drug is primarily dependent upon its rate and extent of drug absorption and systemic clearance. Systemic clearance is primarily composed of hepatic, renal and biliary clearance. The PK properties are in turn directly impacted by the drug s physical properties, such as, log P, log D and pKa. The physical properties are in turn a function of the compound s structure, molecular weight, number of hydrogen bond donors and acceptors, and number of rotatable bonds. Oral bioavailability is the outcome from the dynamic interplay of these factors in the biological system. 

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. 

This volume gives an overview of the current status and an outlook to future more reliable predictive approaches. It is subdivided in five sections dealing with studies of membrane permeability and oral absorption, drug dissolution and solubility, the role of transporters and metabolism in oral absorption, computational approaches to drug absorption and bioavailability, and finally with certain drug development issues. 

There is little quantitative information regarding influence of impaired renal function on drug absorption and bioavailability. 

In the last two decades, the concept of bioavailability has gained prominence and with it dissolution as a possible in vitro model for drug absorption. In 1960, Swintosky and Blythe199... 

As most drugs are preferably given orally, absorption which is complete, consistent and predictable is desirable. Although it may be possible from solubility, lipophilicity, pKa, molecular size, and animal data to make some prediction about likely absorption, only a study in humans will give quantitative data as the mechanisms of drug absorption are complex and still incompletely understood (Washington et al., 2001). It may be helpful here to distinguish between the terms absorption and bioavailability. ... 

Maximum plasma concentration, CmaK, is a measure of both the rate and extent of drug absorption. It is also an essential component of the bioavailability... 

The Time for Maximum Concentration, 7max, is the third important component of bioavailability studies. It is a measure of the rate of drug absorption. A lower 7max represents a faster absorption and a higher Tmax represents a slower absorption. Similar to Cmax, the 7max is read directly from the plasma concentration versus time profile. The 7max in Figure 12.2 is 6 hours. 

Also included in in vivo data is a set of human (90% of drugs) and animal pharmacokinetic (30% of drugs) data. While the in vitro data are generated in-house (Cerep), pharmacokinetic data are gathered from the literature. A variety of different parameters are covered including absolute bioavailability, oral absorption, clearance, volume of distribution, half-life, protein binding and excretion information. 

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