Influence of Drug Formulation on OATP1B-Mediated Transport of Paclitaxel

Abstract

Purpose Taxane antineoplastic agents are extensively taken up into hepatocytes by OATP1B-type transporters prior to metabolism and excretion. Because the biodistributional properties imposed upon these agents by different solubilizers drive clinically-important pharmacodynamic endpoints, we tested the hypothesis that the in vitro and in vivo interaction of taxanes with OATP1B transporters is affected by the choice of drug delivery system. Experimental Design Transport of paclitaxel, docetaxel, and cabazitaxel was studied in vitro using various cell lines transfected with OATP1B1, OATP1B3, or the rodent equivalent Oatp1b2. Pharmacokinetic studies were done in wildtype and Oatp1b2-knockout mice in the presence or absence of polysorbate 80 (PS80) or Kolliphor EL (formerly Cremophor EL; CrEL). Results Paclitaxel and docetaxel, but not cabazitaxel, were transported substrates of OATP1B1, OATP1B3, and Oatp1b2, and these transport processes were strongly reduced in the presence of clinically-relevant concentrations of PS80 and CrEL. In the absence of solubilizers, deficiency of Oatp1b2 in mice was associated with a significantly decreased taxane clearance due to a liver distribution defect (P<0.00001), but these kinetic changes were masked in the presence of PS80 or CrEL (P>0.05). Conclusions Our findings confirm the importance of OATP1B-type transporters in the hepatic elimination of taxanes, and that this process can be inhibited by PS80 and CrEL. These results suggest that the likelihood of drug-drug interactions mediated by these transporters is strongly dependent on the selected taxane solubilizer.

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

“…Indeed, transmembrane transport of taxanes is now widely acknowledged to be mediated by specific OATPs. In particular, we previously reported that paclitaxel and docetaxel are transported substrates of human OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3) (14)(15)(16)(17), as well as the single functional homolog OATP1B2 (Slco1b2) in mice (18) and rats (18,29). These findings have been independently verified (30)(31)(32)(33)(34), and are consistent with in vitro studies that have identified paclitaxel as a potent inhibitor of OATP1B1-(35, 36) and OATP1B3-mediated transport (35,37,38).…”

“…Following this chronic regimen, we found that OATP1B2 -/-mice were also protected against paclitaxelinduced thermal hyperalgesia ( Figure 2E) and changes in digital nerve maximal action potential amplitude (AMP) ( Figure 2F). In support of a functional involvement of OATP1B2 in the paclitaxelinduced toxicity, it is noteworthy to point out that the taxane cabazitaxel, the usage of which is very rarely associated with peripheral neuropathy (22), is not transported by OATP1B-type carriers (18).…”

“…Paclitaxel is known to extensively accumulate in DRG and can be taken up into cells via a process mediated by specific organic anion-transporting polypeptides (OATPs), in particular OAT-P1B1 (SLCO1B1) and OATP1B3 (SLCO1B3) in humans (14)(15)(16)(17) and OATP1B2 (Slco1b2) in rodents (18). To directly demonstrate a contribution of this transport system to paclitaxel toxicity, we used a mouse model with and without deletions of OATP1B2 (OATP1B2 -/-mice).…”

“…These studies demonstrated that the average systemic exposure, measured by the area under the curve (AUC) in plasma, after the administration of a clinically relevant dose of paclitaxel was only modestly increased in OATP1B2 -/-mice (Figure 2A), whereas the observed terminal halflives of paclitaxel were not dependent on mouse genotype (Supplemental Table 2). This suggests that, from a pharmacokinetic perspective, these mice are an appropriate model of human patients (18), with the knowledge that potentially genotype-dependent differences in systemic exposure are unlikely to directly affect the extent to which paclitaxel can induce peripheral neuropathy. We also found that, as reported previously with docetaxel (15), genetic deficiency of OATP1B2 in mice results in decreased liver uptake of paclitaxel, as well as decreased uptake into DRG ( Figure 2B).…”

Inter-patient variability in docetaxel pharmacokinetics: A review

“…Iusuf and colleagues recently found that OATP1A2 was also involved in the in vivo uptake of docetaxel [10]. Animal studies with the OATP1B3/OATP1B1 orthologue OATP1B2 showed that the CL of docetaxel is substantially decreased in OATP1B2 knockout mice [8,10,20,21] in a manner that resembles drug phenotypes observed in mice with a deficiency of metabolic Cyp3a activity [22]. Therefore, co-medication that inhibits both OATP1B1 and 1B3 should only be used with caution in combination with docetaxel.…”