LETTER TO THE EDITOR R-warfarin anticoagulant effect Correspondence Roberto Padrini, Dipartimento di Medicina – DIMED, Università degli Studi di Padova, via Giustiniani 2, 35128 Padova, Italy. Tel.: +39 049 8218332; Fax: +39 049 8212827; E-mail: roberto.padrini@unipd.it Received 13 February 2017; Revised 27 March 2017; Accepted 4 April 2017 Roberto Padrini 1 and Luigi Quintieri 2 1 Dipartimento di Medicina – DIMED, Università degli Studi di Padova, via Giustiniani 2, 35128 Padova, Italy and 2 Dipartimento di Scienze del Farmaco – DSF, Università degli Studi di Padova, via Marzolo 5, 35131 Padova, Italy Keywords modelling and simulation, pharmacodynamics, R-warfarin Tables of Links TARGETS Enzymes [2] vitamin K epoxide reductase complex subunit 1 CYP2C9 LIGANDS Warfarin These Tables list key protein targets and ligands in this article that are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY [1], and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 [2]. Xue et al. [3] have recently studied the pharmacodynamic interaction between S-warfarin (SW) and R-warfarin (RW) in a Chinese population on anticoagulant treatment with a 1.5–2.5 international normalized ratio (INR) target. The authors used a sigmoid maximal effect (E max ) pharmacokinetic–pharmacodynamic (PKPD) model to correlate SW and RW plasma concentrations with INR, and a turnover model to describe the synthesis and elimination of prothrombin complex activity (PCA) in relation to INR. They first hypothesized that RW and SW were full inhibitors of the vitamin K1 epoxide reductase complex 1 (VKORC1) at different potencies [half-maximal effective concentrations (EC 50 s)] but were later obliged to reject this view, as this model yielded a negative estimate of the EC 50 for RW. They then examined RW as a competitive antagonist of SW and calculated a half-maximal inhibitory concentration (IC 50 ) of 2.36 mg l –1 . The scientific debate on the contribution of the RW-to- SW effect is a long and conflictual story. Some studies were unable to show any pharmacological activity of RW after administration of rac-warfarin (racW) in man [4, 5], but others demonstrated that RW, given alone or together with SW, has a definite anticoagulant effect (although lower than that of SW) [6–8] (see Table 1). In particular, a recent study by Maddison et al. [8] has shown that the pharmacodynamic response to racW 25 mg (a mixture of equal amounts of SW and RW) was nearly twice that of SW 12.5 mg given alone, thus indicating the substantial contribution of RW to the racW effect. In addition, an in silico study with computational modelling [9] showed that VKORC1 has two binding sites for SW and RW: site 1 with a higher affinity for SW compared with RW [dissociation constant (Kd) 0.44 μmol l –1 vs. 2.36 μmol l –1 ], which is responsible for the W effect, and site 2 with similar low affinity for both enantiomers (Kd 5.62 μmol l –1 vs. 5.50 μmol l –1 ). In view of this, the more potent SW is expected to displace the less potent RW from site 1, rather than vice versa. Other findings of the study by Xue et al. seem to be difficult to reconcile with present pharmacological knowledge. One is that plasma clearance of RW is paradoxically higher in “slow metabolizers” for cytochrome British Journal of Clinical Pharmacology Br J Clin Pharmacol (2017) 83 2303–2304 2303 © 2017 The British Pharmacological Society DOI:10.1111/bcp.13300