Models to Predict Unbound Intracellular Drug Concentrations in the Presence of Transporters

Korzekwa, Kenneth R.; Nagar, Swati; Tucker, Jalia; Weiskircher, Erica A.; Bhoopathy, Siddhartha; Hidalgo, Ismael J.

doi:10.1124/dmd.111.044289

Cited by 51 publications

(49 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other hand, monkeys had lower oral bioavailability (F = 0.16) than humans (F = 0.53), which was probably due to low absorption from the gut lumen and/or metabolism in the intestine (F A ·F G = 0.25). Pitavastatin is also a substrate of efflux transporters and metabolic enzymes, such as P-gp, breast cancer resistance protein (BCRP), multidrug resistance-associated protein 2 (MRP2), CYP2C, and UGT in humans (Yamada et al, 2003;Hirano et al, 2005Hirano et al, , 2006Uno et al, 2007;Korzekwa et al, 2012). Also, mRNA expression of monkey orthologs of the transporters and the monkey CYP2C in the gastrointestinal tract of cynomolgus monkeys has been reported (Nakanishi et al, 2010;Utoh et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Pitavastatin as an In Vivo Probe for Studying Hepatic Organic Anion Transporting Polypeptide-Mediated Drug–Drug Interactions in Cynomolgus Monkeys

et al. 2013

View full text Add to dashboard Cite

Drug-drug interactions (DDIs) caused by the inhibition of hepatic uptake transporters such as organic anion transporting polypeptide (OATP) can affect therapeutic efficacy and cause adverse reactions. We investigated the potential utility of pitavastatin as an in vivo probe substrate for preclinically studying OATP-mediated DDIs using cynomolgus monkeys. Cyclosporine A (CsA) and rifampicin (RIF), typical OATP inhibitors, inhibited active uptake of pitavastatin into monkey hepatocytes with half-maximal inhibitory concentration values comparable with those in human hepatocytes. CsA and RIF increased the area under the plasma concentration-time curve (AUC) of intravenously administered pitavastatin in cynomolgus monkeys by 3.2-and 3.6-fold, respectively. In addition, there was no apparent prolongation of the elimination half-life of pitavastatin due to the decrease in both hepatic clearance and volume of distribution. These findings suggest that DDIs were caused by the inhibition of hepatic uptake of pitavastatin. CsA and RIF increased the AUC of orally administered pitavastatin by 10.6-and 14.8-fold, respectively, which was additionally caused by the effect of the CsA and RIF in the gastrointestinal tract. Hepatic contribution to the overall DDI for oral pitavastatin with CsA was calculated from the changes in hepatic availability and clearance, and it was shown that the magnitude of hepatic DDI was comparable between the present study and the clinical study. In conclusion, pharmacokinetic studies using pitavastatin as a probe in combination with drug candidates in cynomolgus monkeys are useful to support the assessment of potential clinical DDIs involving hepatic uptake transporters.

show abstract

Section: Discussionmentioning

confidence: 99%

Pitavastatin as an In Vivo Probe for Studying Hepatic Organic Anion Transporting Polypeptide-Mediated Drug–Drug Interactions in Cynomolgus Monkeys

et al. 2013

View full text Add to dashboard Cite

show abstract

“…On the basis of our assessment, repaglinide is categorized as a biopharmaceutics class I drug (Wu and Benet, 2005;Varma et al, 2012a) exhibiting high permeability (Caco-2 permeability ;26 Â 10 26 cm/s), moderate solubility (68 mg/ml) (Mandic and Gabelica, 2006), low dosing (,4 mg), and complete absorption (.95%). Thus, while repaglinide has been shown to be a P-gp substrate with high asymmetric transport across MDCK-MDR1 cells (Korzekwa et al, 2012), P-gp is expected to have a limited role in determining the extent of repaglinide absorption (Varma et al, 2005). On the other hand, the full inductive effect is believed to be attained in about 7 days after once-daily rifampicin treatment (Niemi et al, 2003a).…”

Section: Discussionmentioning

confidence: 99%

Quantitative Prediction of Repaglinide-Rifampicin Complex Drug Interactions Using Dynamic and Static Mechanistic Models: Delineating Differential CYP3A4 Induction and OATP1B1 Inhibition Potential of Rifampicin

Varma

Lin

et al. 2013

Drug Metab Dispos

View full text Add to dashboard Cite

Repaglinide is mainly metabolized by cytochrome P450 enzymes CYP2C8 and CYP3A4, and it is also a substrate to a hepatic uptake transporter, organic anion transporting polypeptide (OATP)1B1. The purpose of this study is to predict the dosing time-dependent pharmacokinetic interactions of repaglinide with rifampicin, using mechanistic models. In vitro hepatic transport of repaglinide, characterized using sandwich-cultured human hepatocytes, and intrinsic metabolic parameters were used to build a dynamic whole-body physiologically-based pharmacokinetic (PBPK) model. The PBPK model adequately described repaglinide plasma concentration-time profiles and successfully predicted area under the plasma concentration-time curve ratios of repaglinide (within 6 25% error), dosed (staggered 0-24 hours) after rifampicin treatment when primarily considering induction of CYP3A4 and reversible inhibition of OATP1B1 by rifampicin. Further, a static mechanistic "extended net-effect" model incorporating transport and metabolic disposition parameters of repaglinide and interaction potency of rifampicin was devised. Predictions based on the static model are similar to those observed in the clinic (average error ∼19%) and to those based on the PBPK model. Both the models suggested that the combined effect of increased gut extraction and decreased hepatic uptake caused minimal repaglinide systemic exposure change when repaglinide is dosed simultaneously or 1 hour after the rifampicin dose. On the other hand, isolated induction effect as a result of temporal separation of the two drugs translated to an approximate 5-fold reduction in repaglinide systemic exposure. In conclusion, both dynamic and static mechanistic models are instrumental in delineating the quantitative contribution of transport and metabolism in the dosing time-dependent repaglinide-rifampicin interactions.

show abstract

“…CL ae was then scaled based on hepatocellularity for subsequent modeling. Initial estimates for metabolic clearance (CL m ), diffusional influx clearance into the membrane (CL i ), and active basolateral uptake clearance (CL bu ) were obtained from the literature and scaled up to the organ level (Lau et al, 2006;Watanabe et al, 2010;Korzekwa et al, 2012). Backdiffusion from the bile into the liver was assumed to be minimal.…”

Section: Mathematical Modeling and Simulationmentioning

confidence: 99%

“…We have previously developed a five-compartment (5-C) model with explicit membranes. Processes such as membrane partitioning (and resulting experimental lag times) and transport out of the membrane can be accurately modeled with the inclusion of explicit membrane compartments (Knipp et al, 1997;Korzekwa et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Intracellular Unbound Atorvastatin Concentrations in the Presence of Metabolism and Transport

Kulkarni¹,

Korzekwa²,

Nagar³

2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Accurate prediction of drug target activity and rational dosing regimen design require knowledge of drug concentrations at the target. It is important to understand the impact of processes such as membrane permeability, partitioning, and active transport on intracellular drug concentrations. The present study aimed to predict intracellular unbound atorvastatin concentrations and characterize the effect of enzyme-transporter interplay on these concentrations. Single-pass liver perfusion studies were conducted in rats using atorvastatin (ATV, 1 mM) alone at 4°C and at 37°C in presence of rifampin (RIF, 20 mM) and 1-aminobenzotriazole (ABT, 1 mM), separately and in combination. The unbound intracellular ATV concentration was predicted with a five-compartment explicit membrane model using the parameterized diffusional influx clearance, active basolateral uptake clearance, and metabolic clearance.Chemical inhibition of uptake and metabolism at 37°C proved to be better controls relative to studies at 4°C. The predicted unbound intracellular concentration at the end of the 50-minute perfusion in the 1ABT , 1ABT1RIF, and the ATV-only groups was 6.5 mM, 0.58 mM, and 5.14 mM, respectively. The predicted total liver concentrations and amount recovered in bile were within 0.94-1.3 fold of the observed value in all groups. The fold difference in total liver concentration did not always extrapolate to the fold difference in predicted unbound concentration across groups. Together, these results support the use of compartmental modeling to predict intracellular concentrations in dynamic organ-based systems. These predictions can provide insight into the role of uptake transporters and metabolizing enzymes in determining drug tissue concentrations.

show abstract

Models to Predict Unbound Intracellular Drug Concentrations in the Presence of Transporters

Cited by 51 publications

References 23 publications

Pitavastatin as an In Vivo Probe for Studying Hepatic Organic Anion Transporting Polypeptide-Mediated Drug–Drug Interactions in Cynomolgus Monkeys

Pitavastatin as an In Vivo Probe for Studying Hepatic Organic Anion Transporting Polypeptide-Mediated Drug–Drug Interactions in Cynomolgus Monkeys

Quantitative Prediction of Repaglinide-Rifampicin Complex Drug Interactions Using Dynamic and Static Mechanistic Models: Delineating Differential CYP3A4 Induction and OATP1B1 Inhibition Potential of Rifampicin

Intracellular Unbound Atorvastatin Concentrations in the Presence of Metabolism and Transport

Contact Info

Product

Resources

About