TABLE 3

Inhibitory properties and pharmacokinetic parameters of drugs coadministered with rosuvastatin in a clinical interaction study

Perpetrator DrugDoseMW[I2]BCRP Ki[I2]/Ki Ratio[Igut max]Cmax totalfu[Iinlet max u]OATP1B1 KiBiliary BCRP
Iinlet max u / Ki Ratio
mgμMμMμMμMμMμM
Fostamatinib100578.526910.0513,820
R4060.031581.90.0180.289>109.3
Eltrombopag75442.56782.132329a17.70.010.2362.7b0.11
Darunavir600547.734382755873c10.6d0.051.2614.30.02
Lopinavir400628.825458.729342e14.60.020.4620.430.05
Clopidogrel75321.99326315780.00990.02f0.3111.80.005
Clopidogrel300321.9372863593110.1300.02f1.2451.80.02
Ezetimibe10409.4982.9342.4g0.0140.100.0502.20.02
Fenofibrate/fenofibric acid67360.837431704.46225.80.010.39820hNA
Fluconazole200306.32612No inhibitionNA21834.6f0.8969.536No inhibitionNA
  • Cmax total, mean steady-state maximum plasma concentration for total (bound plus unbound) drug measured in the clinical interaction study with rosuvastatin; fu, fraction unbound [taken from the drug label accessed via the Pharmapendium database (http://www.pharmapendium.com)]; I2, maximal theoretical gastrointestinal concentration (calculated from dose [mol]/250 ml); Igut max, maximum enterocyte concentration, calculated as (Fa × ka × dose/Qent), where Fa is the fraction absorbed (as default taken to be 1.0), ka is the absorption rate constant (as default taken to be 0.1 min−1), and Qent is the enterocyte blood flow (300 ml/min ≡ 18 l/h; Agarwal et al., 2013); Iinlet max u, maximum unbound liver inlet concentration, calculated as fu × [(Cmax total) + (Fa × ka × dose/Qh)], where Fa is the fraction absorbed (as default taken to be 1.0), ka is the absorption rate constant (as default taken to be 0.1 min−1), and Qh is hepatic blood flow (1500 ml/min); Ki, absolute inhibition constant (assuming competitive inhibition; equates to IC50 in these assays as probe substrate concentration used is < <<< Km); MW, molecular weight [taken from the drug label accessed via Pharmapendium database (http://www.pharmapendium.com)]; NA, not applicable.

  • a Value for Fa taken to be 0.52 (drug label).

  • b Value taken from Allred et al. (2011).

  • c Value for ka taken to be 0.02 (Arab-Alameddine et al., 2014).

  • d Value taken from Kakuda et al. (2011).

  • e Value for ka taken to be 0.02 (Duangchaemkarn and Lohitnavy, 2013).

  • f Value taken from drug pharmacokinetic profile on the University of Washington Drug Interaction Database (http://www.druginteractioninfo.org).

  • g Value for ka taken to be 0.03 (Ezzet et al., 2001).

  • h Value for fenofibric acid taken from Yamazaki et al. (2005).