S-warfarin

Cytochrome P450 2C9 is a mixed-function oxidase localized in the endoplasmic reticulum which is responsible for the biotransformation of several nonsteroidal anti-inflammatory diugs, S-warfarin, several sulfonylurea antidiabetics and other diugs. 

Cytochrome P450 2C9 Low activity in about 10% (heterozygotes) and very low activity in about 0.8% (homozygotes) of Caucasian populations. Prolonged action of several CYP2C9 inactivated drugs like phenytoin, tolbutamide, ibuprofen, or S-warfarin. 

How will you manage BA s warfarin therapy Outline a plan including specific dose changes, timing of monitoring, and patient education. 

Rettie, A. E. etal. (1994). Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics, 4, 39 42. 

The enantioselective reduction of unsaturated alcohol derivatives has been applied to the synthesis of several biologically active compounds (Scheme 24.12). Warfarin (123, R=H) is an important anticoagulant that is normally prescribed as the racemate, despite the enantiomers having dissimilar pharmacological profiles. One of the earliest reported uses of DuPhos was in the development of a chiral switch for this bioactive molecule, facilitating the preparation of (R)- and (S)-warfarin [184]. Although attempted reduction of the parent hydroxycoumarin 122 (R=H) led to formation of an unreactive cyclic hemiketal, hydrogenation of the sodium salt proceeded smoothly with Rh-Et-DuPhos in 86-89% ee. 

Rettie AE, Korzekwa KR, Kunze KL, et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450 a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol 1992 5(1 ) 54—59. 

Kunze KL, Eddy AC, Gibaldi M, et al. Metabolic enantiomeric interactions the inhibition of human (S)-warfarin-7-hydroxylase by (R)-warfarin. Chirality 1991 3(1 ) 24—29. 

CYP2C9 is the major CYP2C enzyme expressed in human liver [35] and plays a major role in the metabolism of numerous therapeutics including many weak acidic drugs such as the nonsteroidal anti-inflammatory compounds (e.g. flurbiprofen) [36] and antidiabetics (e.g. tolbutamide) [37]. In addition, CYP2C9 also metabolizes (S)-warfarin [38], lornoxicam [39] and phenytoin [37]. 

Figure 9.3 The effects of varying levels of accessory proteins on CYP2C9 kinetics using diclofenac (a) or (S)-warfarin (b) as substrate probe [219].

Figure 14.1 (S)-Warfarin-binding site and protein-ligand interactions as observed in the pdb entry log5. The ligand is located too far away from the heme moiety to establish direct interactions. However, it is well positioned to offer additional interactions for other molecules...

We thank Gerhard Wolber from Inte Ligand GmbH for providing the depiction of (S)-warfarin in P450 2C9, a functionality that will be available in a future release of LigandScout. 

Miller, J. H., Erey, R., Hong, J. and Hidy, B. J., Quantitation of R-Warfarin and S-Warfarin in Human Plasma via HPLC with MS/MS Detection, American Society for Mass Spectrometry 2002 Conference Abstract, Orlando, EL, USA, 2002. 

Fig. 14.8 Experimental ligand interactions with cytochrome P450 2C family. (A) X-ray structure ofthe sulfaphenazole derivate DMZ in rabbit CYP2C5 at 2.3 A resolution (PDB 1 N5B) from Wester et al. [191]. Only one ofthe two-ligand orientations for DMZ in accord with electron density is shown placing the benzylic methyl group in a 4.4 A distance to the heme iron. (B) X-ray structure of S-warfarin in human CYP2C9 at 2.55 A resolution (PDB 10G5) from Williams et al. [192]. The substrate is situated in a predominantly hydrophobic pocket. This binding mode places the 6- and 7-hydroxylation sites 10 A from the iron (arrow).

The Ki for HSA binding to racemic warfarin has been reported for 3-6 pM by various techniques, including frontal analysis and equilibrium dialysis, and is temperature- and pH-dependent. See Loun, B., Hage, D.S. Chiral separation mechanisms in protein-based HPLC columns. 1. Thermodynamic studies of (R)- and (S)-warfarin binding to immobilized human serum albumin. Anal. Chem. 1994, 66, 3814-3822. 

R)- and (S)-warfarin are in their bound forms. This takes place within the protein human serum albumin. (Adapted from Clarke et ah, 2001)... 

S)-warfarin were used as the templates. This substrate superposition was supported by an NMR study measuring distances between the heme-iron and the substrate protons (66). The model featured (1) anionic heteroatom (A-) at a distance of approx 4 A from a hypothetical cationic site (C+) of the protein,... 

D pharmacophore models for competitive inhibitors of CYP2C9 were built using Catalyst (173). Three different metabolic reactions, diclofenac 4 -hydroxylation, (S)-warfarin 7-hydroxylation, and tolbutamide 4-hydroxylation, were considered. The general characteristics of the three models were similar with distances between a hydrogen bond acceptor and a second hydrogen bond acceptor/donor being 3.4—5.7 A and the hydrophobic feature was positioned... 

Values were back calculated from actual in vivo DDI data for fluconazole and S-warfarin (fee, CYP2C9 = 0.91), fluvoxamine and theophylline (fcL,CYPiA2 = 0.8), fluvoxamine and S-mephenytoin (fcL,CYP2C9 = 1). ketoconazole and midazolam fcL,CYP3A,hepatic = 0.93), and quinidine and desipramine (fcL,CYP2D6 = 0.9). 

Answer The half-life of amiodarone is 35 days. Approximately five half-Uves are required for functionally complete drug elimination. Thus, it will take approximately 6 months (5 half-lives) before the amiodarone is eliminated from the body. Since amiodarone strongly inhibits metabolism of S-warfarin (active enantiomer), it will continue to affect warfarin metabolism for 6 months following discontinuation of amiodarone. Thus, the dose of warfarin will have to be monitored approximately every month and adjusted if necessary. This monthly monitoring should be continued for at least 6 months, until the metabolism of warfarin stabilizes and a constant dose of warfarin can again be maintained. 

Commercial warfarin is a racemic mixture of S- and R-enantiomers S-warfarin is more potent than R-war-farin. 

D) The gastric enzymes needed to convert R-warfarin into S-warfarin are unstable near plastic. 

C9 Celecoxib, flurbiprofen, hexobarbital, ibuprofen, losartan, phenytoin, tolbutamide, trimethadione, sulfaphenazole, S-warfarin, ticrynafen Barbiturates, rifampin Tienilic acid, sulfaphenazole... 

Warfarin is generally administered as the sodium salt and has 100% bioavailability. Over 99% of racemic warfarin is bound to plasma albumin, which may contribute to its small volume of distribution (the albumin space), its long half-life in plasma (36 hours), and the lack of urinary excretion of unchanged drug. Warfarin used clinically is a racemic mixture composed of equal amounts of two enantiomorphs. The levorotatory S-warfarin is four times more potent than the dextrorotatory R-warfarin. This observation is useful in understanding the stereoselective nature of several drug interactions involving warfarin. 

Stereoselectively inhibits the oxidative metabolism of the S-warfarin enantiomorph of racemic warfarin. 

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