Metabolic stability oral bioavailability

Mandagere, A. K., T. N. Thompson, and K. K. Hwang. Graphical model for estimating oral bioavailability of drugs in humans and other species from their Caco-2 permeability and in vitro liver enzyme metabolic stability rates, J. Med. Chem. 2002, 45, 304-311... 

This model integrates existing in vitro data, such as Caco-2 permeability (Papp) and metabolic stability in liver S9 or microsomes, to estimate bioavailability as being either low, medium, or high. Oral bioavailability predictions for not only humans but also other species can be made by using the metabolic stability values of drugs in liver microsomal enzyme preparations from that species. A premise of this model is that metabolic clearance is more important than renal or biliary clearance in determining bioavailability. However, despite the lack of in vitro renal... 

Fig. 19.10. Oral bioavailability estimates of drugs in rat, guinea pig, dog and human from their respective Caco-2 Papp and metabolic stability in liver microsomes or S9. (Reproduced with permission from Ref. [26], 2002 American Chemical Society.)...

An important DMPK property of a NCE is oral bioavailability (F) of the compound in various pre-clinical species.3 The oral bioavailability of a compound is dependent on several factors including intestinal permeability (estimated by the Caco-2 assay) and hepatic clearance (estimated with an in vitro metabolic stability assay).3 30 The metabolic stability assay is typically performed by incubating test compounds in liver microsomes or hepatocytes. The results can provide estimates of in vivo stability in terms of metabolic liabilities.3 8 59 62 Several authors described this assay as an important tool for the rapid assessment of the DMPK properties of NCEs.3 6 8111819 26 44 59 62-65... 

In addition, compound 15 also had good metabolic stability in human liver microsome in vitro assay (hLM ti/2 = 39min) and in rat in vivo pharmacokinetic studies (ty2 = 3.3 h, po), with a rat oral bioavailability of 15%, showing a significant improvement in these PK parameters over the lead compound 1. The observed improvement in PK during the optimization was another validation of the strategy discussed above. This part of the optimization process is summarized in Scheme 19.2. 

Single Test Compound Clustering with Several Marketed Drugs on the Basis of the Similarity of In Vitro Profile Results Including Human Absorption, Oral Bioavailability, Permeability, Solubility, Log D, and Metabolic Stability Characteristics... 

Compound Solubility (gM) Log D Apparent Permeability (10-6 cm/sec) Metabolic Stability (% Remaining) Oral Bioavailability (%) Absorption (%)... 

Accordingly, the metabolic stability of BP 2.94 in vivo was strikingly enhanced as compared to the active drug. Following oral application of BP 2.94 (36) to healthy human volunteers, the progressive hydrolysis of the prodrug led to a parallel decrease in plasma levels of both compounds. A plasma half-life of 1 h was obtained for liberated (/ )-a-methylhistamine (12) and > 24 h for BP 2.94 (36) as compared to 3 min for non-derivatized (7 )-a-methylhistamine (12). The bioavailability in healthy human volunteers expressed as area under the curve (AUC) of (/ )-a-methylhistamine (12) was about 100-fold increased after oral application of BP 2.94 (36) at a dose of... 

Most peptides and proteins are currently formulated as parenteral formulations because of their poor oral bioavailability. Nevertheless, oral delivery of peptides and proteins would be the preferred route of administration if bioavailability issues could be overcome, as it offers the advantages of convenient, pain-free administration. Although various factors such as permeability, chemical and metabolic stability and gastrointestinal transit time can affect the rate and extent of absorption of orally administered peptides and proteins, molecular size is generally considered the ultimate obstacle [36]. 

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