Drug design absorption

Yee, S. and G. L. Amidon. Oral absorption of angiotensin-converting enzyme inhibitors and peptide prodrugs. In Peptide-based Drug Design. G. L. Amidon (ed), American Chemistry Society, Washington DC 1995, 137-147. 

Figure 2.3 Schematic diagram of the method approach in optimising the drug design for passive absorption by determining the additional hpophihcity required to raise the absorption rate constant of the lead candidate in dilute solution to >90% of the maximum (Adapted from Ho et al. [5]).

The present volume of the series Methods and Principles in Medicinal Chemistry focuses on the impact of pharmacokinetics and metabolism in Drug Design. Pharmacokinetics is the study of the kinetics of absorption, distribution, metabolism, and excretion of drugs and their pharmacologic, therapeutic, or toxic response in animals and man. 

Aqueous solubility is typically inversely proportional to lypophilicity. Lypophilicity represents the affinity of a molecule (or moiety) for a lypophilic environment. Dmg solubility is also an important attribute to its oral absorption and subsequent permeability through membranes. In medicinal chemistry, solubility for a 1-mg kg dose of 5,50, and 500 p,g mL is estimated to be low, medium, and high, respectively (Van de Waterbeemd, 2002). Solubility characteristics have long been recognized as important in pharmaceutical chemistry and are part and parcel of the drug design process. For example, the solubility can be used to determine the maximal absorbable dose (MAD), that is. 

They found that with regard to absorption, which is primarily passive in fish, compounds that are ionized are less likely to be taken up than neutral compounds, and that increased bioavailability was a function of molecular weight (<500), logPe/w (<5), H-bond acceptors (<4—5), and H-bond donors (<7-10) based on drug design from Lipinski s rule of five [57, 58]. de Wolf et al. [59] recommended that compounds with a molecular length of >4.3 nm indicates no uptake or bioconcen-... 

Okabe, H., et al. 1989. Effect of limonene and related compounds on the percutaneous absorption of indomethacin. Drug Design Del 4 313. 

Composite parameter reflecting solubility, absorption, and 1st pass metabolism of compounds, the significance of which is given above for both drug design and toxicology... 

---