In-vitro transport characteristics discriminate wild-type ABCB1 (MDR1) from ALA893SER and ALA893THR polymorphisms

Genetic variation of the human ABCB1 (P-glycoprotein; MDR1 gene product) efflux transporter is strongly suggested as a determinant factor governing the pharmacokinetics of diverse drugs and xenobiotics. Despite various efforts to associate polymorphisms in ABCB1 to actual clinical effect and transport function, information is still inconsistent or even controversial.

Using membrane vesicle preparation from ABCB1-expressing HighFive insect cells, we report here that saturation kinectic parameters of the frequently occurring ABCB1 triallelic variants 893Ser (exon 21, 2677T) and 893Thr (2677A) were considerably different from wild-type 893Ala (2677G), despite similar protein expression levels. Of importance were significant differences in transport capacities between the tested 893Ala/Ser/Thr variants. In comparison with 893Ala, maximal transport rates for vincristine of 893Ser and 893Thr increased 50% and three-fold, respectively. Cis-inhibition by digoxin, didanosine or fexofenadine was least pronounced in 893Ser, whereas no genotype differences could be observed using verapamil.

These results suggest an influence of ABCB1-893 triallelic variants on transport function and drug-drug interaction, which might be most pronounced in 893Thr. Furthermore, some of the mechanisms of 2677G/T/A-based haplotype-associated alterations in ABCB1 activity may have been unveiled.