Species differences in drug transporters and implications for translating preclinical findings to humans

Abstract

Quantitative knowledge of species differences of transporters, especially at the protein and functional level is still limited. The current challenge is to extrapolate and integrate data from both preclinical species and humans to quantitatively predict the impact of transporters on drug absorption, disposition, and drug-drug interactions. Increased understanding of species differences in transporter expression and functional activity is needed in order to translate findings from preclinical species to humans. Ultimately, high quality in vitro and in vivo data will aid in the establishment of physiologically based pharmacokinetic (PBPK) models, which will improve the capability to predict PK characteristics of drug candidates in humans.

Interindividual Variability in Hepatic Organic Anion-Transporting Polypeptides and P-Glycoprotein (ABCB1) Protein Expression: Quantification by Liquid Chromatography Tandem Mass Spectroscopy and Influence of Genotype, Age, and Sex

“…To achieve these goals on a population basis, physiologically based pharmacokinetic (PBPK) models (e.g., Simcyp) are increasingly being used in drug development and pharmaceutical research (Varma et al, 2012(Varma et al, , 2013. For drugs where transporters are involved in their disposition, successful use of PBPK models requires critical information on the tissue localization and expression of the transporters, including the effect of covariates, like genotype, age, and sex, on transporter expression (Deo et al, 2012;Chu et al, 2013;Harwood et al, 2013;Prasad et al, 2013). However, such data are currently not available.…”

Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs

“…Oatp1a1, Oatp1a4 and Oatp1b2 are expressed in the rodent liver and Oatp1b4 is expressed in canine liver. 3) Both OATP1B1 and OATP1B3 can accept a wide variety of structurally-unrelated compounds including clinically-used important drugs such as hydroxymethylglutaryl (HMG)-CoA reductase inhibitors (statins), angiotensin II receptor blockers (sartans), angiotensin converting enzyme (ACE) inhibitors, and anti-diabetes (glinides) as substrates. Though OATP transporters preferentially transport anionic compounds, neutral (e.g.…”

Evaluation of P-glycoprotein expression in pain relevant tissues: understanding translation of efflux from preclinical species to human

“…In particular, the reports on the expression of this trans-membrane efflux pump in the spinal cord and DRG have been sparse. The lack of understanding of species differences in expression and functionality of transporters can serve as a bottleneck in the translation of drug disposition from preclinical species to human, particularly, for compounds with the site of action in CNS [16]. Therefore, in an attempt to examine species differences in P-gp expression in various pain relevant tissues, we have looked at the detailed micro-anatomic localization of P-gp in the normal brain, spinal cord and DRG tissues of rat, dog, monkey and human by using immunohistochemistry, immunofluorescence and confocal microscopy.…”