A novel in vitro allometric scaling methodology for aldehyde oxidase substrates to enable selection of appropriate species for traditional allometry

Abstract

1. Failure to predict human pharmacokinetics of aldehyde oxidase (AO) substrates using traditional allometry has been attributed to species differences in AO metabolism.

2. To identify appropriate species for predicting human in vivo clearance by single-species scaling (SSS) or multispecies allometry (MA), we scaled in vitro intrinsic clearance (CL_int) of five AO substrates obtained from hepatic S9 of mouse, rat, guinea pig, monkey and minipig to human in vitro CL_int.

3. When predicting human in vitro CL_int, average absolute fold-error was ≤2.0 by SSS with monkey, minipig and guinea pig (rat/mouse >3.0) and was <3.0 by most MA species combinations (including rat/mouse combinations).

4. Interspecies variables, including fraction metabolized by AO (F_m,AO) and hepatic extraction ratios (E) were estimated in vitro. SSS prediction fold-errors correlated with the animal:human ratio of E (r² = 0.6488), but not F_m,AO (r² = 0.0051).

5. Using plasma clearance (CL_p) from the literature, SSS with monkey was superior to rat or mouse at predicting human CL_p of BIBX1382 and zoniporide, consistent with in vitro SSS assessments.

6. Evaluation of in vitro allometry, F_m,AO and E may prove useful to guide selection of suitable species for traditional allometry and prediction of human pharmacokinetics of AO substrates.

Keywords:

• Aldehyde oxidase
• clearance
• drug metabolism
• molybdenum hydroxylase
• pharmacokinetics
• noncytochrome P450
• S9
• species differences

Acknowledgements

The authors thank Professor Craig Lindsley (Vanderbilt University School of Medicine) for access to facilities and resources which enabled completion of this work.

Declaration of interest

The authors report no conflicts of interest. The authors are responsible for the content and writing of the article.

This work was supported by the Pharmaceutical Research and Manufacturers of America Foundation (PhRMA Foundation Pre-Doctoral Fellowship); the National Institutes of Health under Grant T32GM07628; and the Department of Pharmacology, Vanderbilt University School of Medicine.