Statins are the preferred class of drugs for treating patients with atherosclerosis and related coronary heart disease. Treatment with statins leads to significant low-density lipoprotein cholesterol (LDL-C) lowering, resulting in reductions in major coronary and vascular events. Statins are generally well tolerated and safe; however, their use is complicated by infrequent, but often serious, muscular adverse events. For many statins, both efficacy and risk of adverse muscle events can be influenced by membrane transporters, which are important determinants of statin disposition. Genetic polymorphisms and drug-drug interactions (DDIs) involving organic anion-transporting polypeptide 1B1 and breast cancer resistance protein have shown the capacity to reduce the activity of these transporters, resulting in changes in LDL-C lowering by statins, as well as changes in the frequency of adverse muscle events associated with their use. This review presents evidence for how reduced transporter activity impacts the safety and pharmacology of statins. It expands on the scope of other recent statin reviews by providing recommendations on in vitro evaluation of statin interaction potential, discussing how reduced transporter activity impacts statin management during drug development, and proposing ideas on how to evaluate the impact of DDI on statin efficacy during clinical trials. Furthermore, the potential clinical consequences of perturbing statin efficacy via DDI are discussed.

Rosuvastatin is a widely prescribed antihyperlipidemic which undergoes limited metabolism, but is an in vitro substrate of multiple transporters [organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, OATP1A2, OATP2B1, sodium-taurocholate cotransporting polypeptide, breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), MRP4, organic anion transporter 3]. It is therefore frequently used as a probe substrate in clinical drug-drug interaction (DDI) studies to investigate transporter inhibition. Although each of these transporters is believed to play a role in rosuvastatin disposition, multiple pharmacogenetic studies confirm that OATP1B1 and BCRP play an important role in vivo. Ronacaleret, a drug-development candidate for treatment of osteoporosis (now terminated), was shown to inhibit OATP1B1 in vitro (IC = 11 µM), whereas it did not inhibit BCRP. Since a DDI risk through inhibition of OATP1B1 could not be discharged, a clinical DDI study was performed with rosuvastatin before initiation of phase II trials. Unexpectedly, coadministration with ronacaleret decreased rosuvastatin exposure by approximately 50%, whereas time of maximal plasma concentration and terminal half-life remained unchanged, suggesting decreased absorption and/or enhanced first-pass elimination of rosuvastatin. Of the potential in vivo rosuvastatin transporter pathways, two might explain the observed results: intestinal OATP2B1 and hepatic MRP4. Further investigations revealed that ronacaleret inhibited OATP2B1 (in vitro IC = 12 µM), indicating a DDI risk through inhibition of absorption. Ronacaleret did not inhibit MRP4, discharging the possibility of enhanced first-pass elimination of rosuvastatin (reduced basolateral secretion from hepatocytes into blood). Therefore, a likely mechanism of the observed DDI is inhibition of intestinal OATP2B1, demonstrating the in vivo importance of this transporter in rosuvastatin absorption in humans.

The BRAF inhibitor dabrafenib was recently approved for the treatment of certain BRAF V600 mutation-positive tumors, either alone or in combination therapy with the mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 inhibitor, trametinib. This article presents the dabrafenib transporter-mediated drug-drug interaction (DDI) risk assessment, which is currently an important part of drug development, regulatory submission, and drug registration. Dabrafenib and its major circulating metabolites (hydroxy-, carboxy-, and desmethyl-dabrafenib) were investigated as inhibitors of the clinically relevant transporters P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, and OAT3. The DDI Guidance risk assessment decision criteria for inhibition of BCRP, OATP1B1 and OAT3 were slightly exceeded and therefore a minor DDI effect resulting from inhibition of these transporters remained possible. Biliary secretion is the major excretion pathway of dabrafenib-related material (71.1% of orally administered radiolabeled dose recovered in feces), whereas urinary excretion was observed as well (22.7% of the dose). In vitro uptake into human hepatocytes of the dabrafenib metabolites, but not of dabrafenib parent compound, was mediated, at least in part, by hepatic uptake transporters. The transporters responsible for uptake of the pharmacologically active hydroxy- and desmethyl dabrafenib could not be identified, whereas carboxy-dabrafenib was a substrate of several OATPs. Dabrafenib, hydroxy-, and desmethyl-dabrafenib were substrates of P-gp and BCRP, whereas carboxy-dabrafenib was not. Although a small increase in exposure to carboxy-dabrafenib upon inhibition of OATPs and an increase in exposure to desmethyl-dabrafenib upon inhibition of P-gp or BCRP cannot be excluded, the clinical significance of such increases is likely to be low.

Although the airway surface is the anatomic target for many lung disease therapies, measuring drug concentrations and activities on these surfaces poses considerable challenges. We tested whether mass spectrometric analysis of exhaled breath condensate (EBC) could be utilized to noninvasively measure airway drug pharmacokinetics and predicted pharmacological activities.Mass spectrometric methods were developed to detect a novel epithelial sodium channel blocker (GS-9411/P-680), two metabolites, a chemically related internal standard, plus naturally occurring solutes including urea as a dilution marker. These methods were then applied to EBC and serum collected from four (Floridian) sheep before, during and after inhalation of nebulized GS-9411/ P-680. Electrolyte content of EBC and serum was also assessed as a potential pharmacodynamic marker of drug activity. Airway surface concentrations of drug, metabolites, and electrolytes were calculated from EBC measures using EBC:serum urea based dilution factors.GS-9411/P-680 and its metabolites were quantifiable in the sheep EBC, with peak airway concentrations between 1.9-3.4 μM measured 1 hour after inhalation. In serum, only Metabolite #1 was quantifiable, with peak concentrations ~60-fold lower than those in the airway (45 nM at 1 hour). EBC electrolyte concentrations suggested a pharmacological effect; but this effect was not statistical significant.Analysis of EBC collected during an inhalation drug study provided a method for quantification of airway drug and metabolites via mass spectrometry. Application of this methodology could provide an important tool in development and testing of drugs for airways diseases.