Functional Consequences of Pravastatin Isomerization on OATP1B1-Mediated Transport

Abstract

Pravastatin (PVA) can be isomerized to its inactive metabolite 3'α-iso-pravastatin acid (3αPVA) under acidic pH conditions. Previous studies reported inter-individual differences in circulating concentrations of PVA and 3αPVA. This study investigated the functional consequences of PVA isomerization on OATP1B1-mediated transport. We characterized 3αPVA inhibition of OATP1B1-mediated PVA uptake into HEK293 cells expressing the four different OATP1B1 proteins (*1a, *1b, *5 and *15). 3αPVA inhibited OATP1B1-mediated PVA uptake in all four OATP1B1 gene products but with lower IC 50 /K i values for OATP1B1*5 and *15 than for the reference proteins (*1a and *1b). PVA and 3αPVA were transported by all four OATP1B1 proteins. Kinetic experiments revealed that maximal transport rates (V max values) for OATP1B1 variants *5 and *15 were lower than for *1a and *1b for both substrates. Apparent affinities for 3αPVA transport were similar for all four variants. However, the apparent affinity of OATP1B1*5 for 3αPVA was higher (lower K m value) than for PVA. These data confirm that PVA conversion to 3αPVA can have functional consequences on PVA uptake and impacts OATP1B1 variants more than the reference protein, thus highlighting another source variation that must be taken into consideration when optimizing the PVA dose-exposure relationship for patients. Significance Statement 3'α-iso-pravastatin acid inhibits pravastatin uptake for all OATP1B1 protein types, however, the IC 50 values were significantly lower in OATP1B1*5 and *15 transfected cells. This suggests that a lower concentration of 3'α-iso-pravastatin is needed to disrupt OATP1B1-mediated pravastatin uptake, secondary to decreased cell surface expression of functional OATP1B1 in variant expressing cells. These data will refine previous pharmacokinetic models that are utilized to characterize pravastatin inter-individual variability with an ultimate goal of maximizing efficacy at the lowest possible risk for toxicity.

Testing of drugs using human feto-maternal interface organ-on-chips provide insights into pharmacokinetics and efficacy

“…Pravastatin and rosuvastatin uptake were facilitated by the organic anion transporting polypeptide transporters and breast cancer resistance protein respectively. 49,52,65 breast cancer resistance protein is highly expressed in the human placenta and facilitates the transport of a wide variety of drugs. 40,66 Since rosuvastatin was efficiently transported by BCRP, the concentration of the rosuvastatin in the STB chamber was decreased.…”

“…[46][47][48] Pravastatin is primarily metabolized (3′α-iso pravastatin, 6′epipravastatin, 3′α, 5′ β-dihydro-pravastatin, desacyl-dehydro pravastatin, 3′-hydroxy-pravastatin) by glucuronidation and minimally involve CYP enzymes. [49][50][51] Rosuvastatin is predominantly metabolized (N-desmethyl rosuvastatin and rosuvastatin-5S-lactone) by CYP 3A4 and 2D6 enzymes. 52 To note, pravastatin metabolites are inactive and often lead to increased excretion, whereas rosuvastatin metabolites are active and carry out its mechanism of action.…”

Rhabdomyolysis-induced acute kidney injury after administration of a red yeast rice supplement: A case report

“…Laboratory studies have shown that statins can limit cancer progression by promoting apoptosis and inflammatory responses and by inhibiting cancer cell proliferation, adhesion, and angiogenesis[ 9 - 12 ]. A meta-analysis reported that patients with mCRPC may benefit from treatment with abiraterone or enzalutamide in combination with statins[ 13 ]. In addition to lowering cholesterol, statins compete to inhibit DHEA uptake by binding to solute carrier transporters (SLCO2B1), thereby effectively reducing the pool of androgens available in tumors.…”

“…Theoretically, this transporter affects the uptake of multiple exogenous drugs, including lovastatin. OATP1B1 inhibition increases lovastatin levels, resulting in increased drug toxicity[ 13 , 14 ]. Statin-induced rhabdomyolysis is dose-dependent, especially when statins are used in conjunction with a muscle-toxic agent or drug that can increase their concentration.…”

PharmVar GeneFocus: SLCO1B1

“…[1][2][3] Genetic variation in SLCO1B1 can result in lower amounts of OATP1B1 protein on the basolateral surface of human hepatocytes, or decreased function resulting in diminished hepatocellular uptake. This, in turn, can limit hepatic clearance and cause increased systemic exposure to drug substrates, [4][5][6][7][8][9] which can lead to increased risk for systemic drug toxicity and adverse events. [10][11][12] Additionally, there is also in vitro and in vivo evidence that some genetic variants increase gene expression and function, as well as variants that impact transporter function in a substrate-dependent manner.…”