Prediction of human renal clearance from preclinical species for a diverse set of drugs that exhibit both active secretion and net re- absorption

Stuart W. Paine, Karelle Ménochet, Rebecca Denton, Dermot F. McGinnity, Robert J. Riley

Table 1

Compound CLR Unbound CLR References Human Dog Rat Human Dog Rat Ampicillin 1.39 3.25 11.80 1.70 3.61 13.11 Shrewsbury, 1986; Goodman and Gilman, 1996; Griffin, 2002 Carbamazepine 0.13 0.53 0.45 0.42b 1.96b 2.24b Morselli and Frigerio, 1975; Remmel et al., 1990; Griffin, 2002; Goodman and Gilman, 2006 Cefazolin 0.76 3.14 4.92 9.27b 4.23b 41.02b Komiya et al., 1981; Sawada et al., 1984; Goodman and Gilman, 2006 Cefclidin 1.47 2.52 8.20 1.61 2.75 9.15 Nakashima et al., 1989; Kita et al., 1992 Cefmetazole 1.54 3.92 7.98 7.96b 4.36b 14.25 Sawada et al., 1984 Cefodizime 0.50 1.13 0.40 1.84 2.51 2.86 Klesel et al., 1984; Barre, 1990; Matsushita et al., 1992 Cefoperazone 1.20 3.24 3.11 6.82 4.11b 4.17 Sawada et al., 1984

Cefotetan 0.15 2.11 6.65 1.03 2.35b 9.45 Komiya et al., 1981; Goodman and Gilman, 2006 Cefozopran 2.55 2.69 6.99 3.68 3.00 7.47 Kita et al., 1992; Paulfeuerborn et al., 1993 Cefpiramide 0.07 3.62 3.35 1.78 5.17 6.21 Sawada et al., 1985 Cefpirome 1.17 2.63 8.32 1.30 2.83 9.88 Kavi et al., 1988; Kita et al., 1992; Sakamoto et al., 1993 Ceftazidime 0.88 2.29 8.41 1.12 2.56 8.83 Kita et al., 1992; Sakamoto et al., 1993; Araki et al., 2002; Goodman and Gilman, 2006 Cimetidine 5.15 6.53 37.65 6.35 7.73 45.06 Griffin, 2002; Goodman and Gilman, 2006 Dolasetron 5.02 4.83 34.0 10.25 10.98 77.27 Sanwald-Ducray and Dow, 1997 Donepezil 0.31 0.26 1.19 2.36b 0.43b 2.84b Matsui et al., 1999; Goodman and Gilman, 2006 Fluconazole 0.20 0.60 0.72 0.24b 0.67 0.81 Humphrey et al., 1985; Jezequel, 1994; Goodman and Gilman, 2006 Furosemide 1.18 11.9 2.83 84.19b 383.94b 141.50b Lee et al., 1986; Jang et al., 1994; Goodman and Gilman, 2006 Gabapentin 1.06 1.54 9.08 1.09 1.59 9.37 Radulovic et al., 1995;

Goodman and Gilman, 2006 Garenoxacin 0.80 0.37 1.65 3.20 1.61 12.60 Gajjar et al., 2003; Hayakawa et al., 2003 Ibuprofen 0.008 0.06a 0.0002a 1.50b 5.83b 0.01b Goodman and Gilman, 2006 Indomethacin 0.21 0.07a 0.001a 22.11b 8.05b 0.50b Goodman and Gilman, 2006 Inogatran 3.05 3.40 15.7 4.01 4.47 20.66 Teger-Nilsson et al., 1995; Eriksson et al., 1998 Levetiracetam 0.63 0.69 2.18 0.70 0.77 2.42 Isoherranen et al., 2001; Benedetti et al., 2004; Goodman and Gilman, 2006 Losartan 0.97 3.03a 0.003a 48.60b 58.72b 0.33b Goodman and Gilman, 2006 Melagatran 1.71 2.98 8.60 2.00 3.33 9.56 Eriksson et al., 1998; Eriksson et al., 2003 Moxalactam 1.25 1.99 7.69 3.13 3.61 15.08 Sawada et al., 1984 Moxifloxacin 0.50 0.37 3.60 0.90 0.52 5.71 Siefert et al., 1999; Goodman and Gilman, 2006 Naproxen 0.004 0.02 0.06 4.00b 7.87b 22.64b Runkel et al., 1972; Sugawara et al., 1978; Griffin, 2002; Goodman and Gilman, 2006 Ramatroban 1.36 1.65a 0.64 56.67b 30.44b 12.57b Insight., ; Boberg et al., 1997 Ranitidine 7.18 10.1 7.78 8.44 14.43 8.64 Boom et al., 1998;

Griffin, 2002; Goodman and Gilman, 2006 Sematilide 3.33 6.10 17.41 3.92b 6.78b 19.34b Hinderling et al., 1993 Sulfinpyrazone 0.08 0.37 0.05 12.02b 6.27b 20.35b Dieterle and Faigle, 1981; Pedersen et al., 1982 Sulfisoxazole 0.13 0.33 0.06 1.15b 0.55 6.00b Yacobi and Levy, 1979; Suber et al., 1981; Oie et al., 1982 Theophylline 0.12 0.82 0.57 0.27 1.46 1.43 Kuze et al., 1988; Poulin and Theil, 2002; Goodman and Gilman, 2006 UK-224,671 0.41 0.90 6.58 0.99 3.21 19.35 Beaumont et al., 2000 UK-240,455 3.66 5.33 6.84 28.15 35.53 228.00 Webster et al., 2003 a: Renal clearances measured in-house. b: Plasma protein binding measured in-house.

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