Interspecies Pharmacokinetic Scaling and Metabolism of Alcohols and Glycols

Background: Despite the numerous pharmaceutical applications of alcohols andglycols, the interspecies differences with respect to their pharmacokinetics (PK) arepoorly understood. The aim of this research was to use in-vivo and in-vitro approaches to compare and model the PK characteristics across various species.Methods: Appropriate published in-vivo studies (in different species) foralcohols and glycols were carefully selected. PK analysis was performed using (a) noncompartmental analysis and (b) compartmental modeling to estimate relevant dose-independent PK parameters. Next, six alcohols (methanol, ethanol, 1 -propanol, 1 -butanol, 1-hexanol, and 1-octanol), two glycols (ethylene glycol and propylene glycol)and one secondary alcohol (2-propanol) were examined as in-vitro substrates for equine ADH using a UV spectrophotometric assay to evaluate the effect of molecular structure. Furthermore, in-vitro metabolism of ethanol and propylene glycol was also characterized in hepatic cytosolic fractions from rat, rabbit, dog and human and in-vitro in-vivo correlation for the hepatic disposition parameters was assessed. Finally, allometric scaling relationships for ethanol and propylene glycol PK parameters (in-vivo and in-vitro) were developed and validated.Results: Alcohols and glycols exhibited nonlinear PK due to saturable hepaticmetabolism in all species. The reported in-vivo data were well described by oneltwo compartment PK models with parallel saturable metabolism and first-order renalexcretion. In-vitro equine ADH experiments revealed differences in affinity andturnover between the substrates: Enzyme affinity (1/Km) and in-vitro intrinsic clearance (CLintin-vitro) correlated positively with logP values; glycols showed lower CLintin-vitro values than straight-chain alcohols. In-vitro hepatic cytosol studies yielded acceptable in-vivo predictions for the metabolic clearance (CLmet) of ethanol and propylene glycol in the rat, dog and human, but not the rabbit. Vdss, Vmax, CLintin-vitro, CLmet scaled allometrically across species with similar powers for both ethanol and propylene glycol, and good agreement between in-vivo and in-vitro scaling was noted. The allometric scaling models gave excellent predictions when externally validated against in-vivo concentration-time data. Conclusions: The present research demonstrates .the successful application of amodeling-based approach to elucidate interspecies relationships for alcohols andglycols, compounds which exhibit nonlinear PK and mainly low hepatic extractionbehavior. The in-vitro experimental systems have been used successfully forcharacterizing alcohol/glycol metabolism and predicting in-vivo disposition.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Pharmaceutics

Year dc:date.available

2006

Author dc:creator

• Gupta, Pankaj

Contributors dc:contributor

• Dr. Jürgen Venitz

• ethanol
• propylene
• hydrophobic drugs
• Medicine and Health Sciences
• Pharmacy and Pharmaceutical Sciences

Statement dc:rights

• © The Author

Identifier

https://scholarscompass.vcu.edu/etd/1015

OAI identifier oai:identifier

oai:scholarscompass.vcu.edu:etd-2014