Stereoselective Interaction of Omeprazole with Warfarin in Healthy Men

Sutfin, T A; Balmér, Karin; Boström, Hans; Eriksson, Sara; Höglund, Peter; Paulsen, Otto

doi:10.1097/00007691-198903000-00010

Cited by 114 publications

(52 citation statements)

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“…Omeprazole has been shown to decrease the clearance of only the Renantiomer of warfarin (Sutfin et al, 1989;Unge et al, 1992). In agreement with these observations we find that the human liver microsomal metabolism of R-but not S-warfarin is inhibited by omeprazole.…”

Section: Discussionsupporting

confidence: 89%

“…Various P450 isozymes, displaying different regio-and stereoselectivities, have been shown to be involved in the metabolism of warfarin (Guengerich et al, 1982;Rettie et al, 1992). The variety of warfarin metabolizing P450 isozymes offers an explanation for the stereoselective (pharmacokinetic) drug-interactions with R-warfarin (Choonara et al, 1986;Toon et al, 1987;Sutfin et al, 1989;), S-warfarin (Lewis et al, 1974;O'Reilly, 1980), as well as non-stereoselective interactions (O'Reilly et al, 1987) that have been observed. The human cytochrome P450 2C9 has been shown to be a S-warfarin 7-(and to a lesser extent 6-) hydroxylase, and is claimed to be responsible for the bulk of S-warfarin clearance in vivo (Rettie et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

“…To investigate whether the set of human liver cytochrome P450 isozymes metabolizing R/S warfarin is similar to that metabolizing R/S acenocoumarol, the inhibiting effects of four drugs (cimetidine, propafenone, sulphaphenazole, and omeprazole) have been studied. Cimetidine and omeprazole were chosen since these compounds are known to decrease the clearance of R-warfarin in man (Choonara et al, 1986;Sutfin et al, 1989;Unge et al, 1992). Sulphaphenazole, was studied because this compound is reported to be a potent inhibitor of human liver cytochrome P450 2C9-mediated Swarfarin 7-hydroxylation (Rettie et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

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Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics

Hermans

Thijssen

1993

British J Pharmacology

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1 To explain the large differences in (the stereoselectivity of) the clearances of the enantiomers of warfarin and acenocoumarol (4'-nitrowarfarin) their human liver microsomal metabolism has been studied and enzyme kinetic parameters determined. The effects of cimetidine, propafenone, sulphaphenazole, and omeprazole on their metabolism has been investigated. 2 The 4-hydroxycoumarins follow similar metabolic routes and are mainly hydroxylated at the 6-and 7-position (accounting for 63 to 99% of the metabolic clearances).3 Due to the lower Km values of R-and S-acenocoumarol and higher Vma. values of S-acenocoumarol, the overall metabolic clearances of R/S acenocoumarol exceed those of R/S warfarin 6 and 66 times respectively. 4 The metabolism of both compounds is stereoselective for the S-enantiomers, which is 10 times more pronounced in the case of acenocoumarol.5 Except for the 7-hydroxylation of the R-enantiomers (r = 0.90; P <0.025), the 6-and 7-hydroxylation rates of R/S warfarin do not correlate with those of R/S acenocoumarol. 6 Sulphaphenazole competitively inhibits the 7-and in some samples partly (up to 50%) the 6-hydroxylation of S-warfarin as well as the 7-hydroxylation of R-and S-acenocoumarol and the 6-hydroxylation of S-acenocoumarol (Kis ranging from 0.5-1.3 JAM).7 Omeprazole partly (40-80%) inhibits the 6-and 7-hydroxylation of R-warfarin (Ki = 99 and 117 pM) and of R-(Ki = 219 and 7.2 jAM) and S-acenocoumarol (Ki = 6.1 and 7.7 JiM) but not S-warfarin in a competitive manner. 8 Differences in the partial (up to 40%) inhibition of the metabolism of the enantiomers of the 4-hydroxycoumarins were also observed for the relatively weak inhibitors, propafenone and cimetidine. 9 The results suggest that the coumarin ring hydroxylations of both compounds are catalysed by different combinations of P450 isozymes. The 7-hydroxylation of R/S acenocoumarol and the 6-hydroxylation of S-acenocoumarol are at least partly conducted by (a) P450 isozyme(s) of the 2C subfamily different from P450 2C9 (the main S-warfarin 7-and 6-hydroxylase).

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics

Hermans

Thijssen

1993

British J Pharmacology

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“…Nizatidine had no effect on the anticoagulant response to warfarin 143 . Omeprazole may inhibit the metabolism of R-warfarin 144 , but the clinically significant effect on activity of warfarin is unlikely. Similarly, pantoprazole appears to have no effect on warfarin 145 .…”

Section: Drugs Causing Inhibition Of Metabolismmentioning

confidence: 99%

Interactions of Warfarin

Rehulková¹

2001

BIOMED PAP

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In this article, the author reviews and updates the basis of interactions with warfarin, illustrated with appropriate examples. The interactions with drugs, medicinal herbs and foods are summarised. 28Cholestyramine binds vitamin K in the gut, thus preventing its absorption 18 . It also decreases the absorption and may interrupt the enterohepatic recirculation of warfarin, resulting in a reduced anticoagulant effect 19,20 .Colestipol does not affect the absorption of warfarin. When colestipol is administered with warfarin, no depressant effects on blood levels are seen 21 . Drugs affecting receptor sensitivityEstrogens increase the synthesis of various clotting factors and may thus reduce the effect of anticoagulants 22, 23 . Oral contraceptives increase clotting factor concentrations and inhibit warfarin metabolism. The net effect depends on balance between these factors. Oral contraceptives are generally contraindicated in most patients taking warfarin since they are trombogenic 1, 24 .Steroids with anabolic or androgenic properties, such as oxymetholone 25, 26, 27 , stanozolol 28, 29 and danazol 30, 31, 32 , may potentiate the action of warfarin allegedly by reducing clotting factor synthesis. The 17-alpha-alkylated steroids appear to be more likely to induce this reaction than the non-substituted steroids 25, 26, 27, 33 . However, there has been a report of topically applied testosterone, which does not have 17-alpha-alkyl substituent, enhancing warfarin 34 .Diuretics may antagonise the action of warfarin by two pharmacodynamic mechanisms 18 : (a) patients in cardiac failure have impaired clotting factor synthesis due to hepatic congestion -correction of this state leads to increased clotting factor synthesis; (b) diuretics also reduce the plasma volume producing an increased concentration of clotting factors which may alter the anticoagulant effect of warfarin 35 . Chlorthalidone 36 and spironolactone 35 have both been associated with a reduction of warfarin activity probably as a consequence of diuresis concentrating the circulating clotting factors. Bumetanide, furosemide and thiazides appear to have no effect on warfarin 23 .Certain cephalosporines, such as cefotetan, cefamandole, cefoperazone, or moxalactam may cause marked hypoprothrombinemia and/or prolonged bleeding time at concurrent use with warfarin 38, 39, 40, 41 . The main mechanism of interaction consists in decreasing synthesis of vitamin K-dependent clotting factors.Clofibrate may potentiate warfarin action, probably by altering receptor sensitivity 23, 37 . Although clofibrate displaces warfarin from albumin binding sites this does not appear to be a principal mechanism of the interaction 42 .Drugs altering thyroid function may affect anticoagulant control, since rates of synthesis and degradation of clotting factors are dependent on thyroid function 7 . Thyroid compounds do enhance the activity of oral anticoagulants by increased metabolism of clotting factors 12 . Dextrothyroxine increases the anticoagulant effect of warfarin ...

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“…(6) Because omeprazole increases the r-warfarin blood levels and reduces thrombosis by 10%, omeprazole should be avoided in patients taking warfarin (7). There is insufficient data on other PPIs.…”

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confidence: 99%

When proton pump inhibitors are compared, are there specific cases in which a certain proton pump inhibitors should be particularly preferred?

Çelebi

Yılmaz

2017

Turk J Gastroenterol

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Proton pump inhibitors (PPI) are currently the most commonly used drugs and have risk for drug interactions in people taking multiple medications. When studies on the risk of drug interactions of PPIs are examined in the literature, it is evident that the most studied subject is the interaction of clopidogrel and PPI.Six meta-analyses were found in the literature regarding the concomitant use of PPIs and clopidogrel. Out of these, in the meta-analysis performed by Huang et al. (1) in which the maximum number (32) of studies were evaluated, an increased risk of major cardiac event (HR 1.40, 95% CI 1.19-1.64; OR 1.27, 95% CI 1.13-1.42) and an increased risk of acute coronary syndrome (HR 1.42, 95% CI 1.14-1.77; OR 1.42, 95% CI 1.08-1.87) were reported. No risk increase has been reported for the total mortality (HR 1.30, 95% CI 0.91-1.86; OR 0.92, 95% CI 0.82-1.04) and cardiovascular death (HR 1.21, 95% CI 0.60-2.43). As a result, the concomitant use of clopidogrel and PPIs increases the risk of major cardiac events, but it has not been shown to influence total mortality (1,2). Although there is insufficient data in the literature, omeprazole and esomeprazole with high affinity of CY-P2C19 should be avoided if PPI are required to be used in patients treated with clopidogrel.Theophylline is often used in combination with PPI in advanced-age populations with respiratory diseases. In reference to the conducted studies, theophylline blood levels are not affected by the concomitant use of lansoprazole or pantoprazole with theophylline (3). Lansoprazole, pantoprazole, and omeprazole do not affect the excretion and absorption of theophylline (4). There is no change in theophylline pharmacokinetics with the use of rabeprazole (5). Treatment change is not needed in patients using theophylline together with lansoprazole, pantoprazole, omeprazole, and rabeprazole. There is no data involving esomeprazole.In the concomitant use of warfarin and pantoprazole, it was found that pantoprazole did not change the pharmacokinetics and pharmacodynamics of warfarin. (6) Because omeprazole increases the r-warfarin blood levels and reduces thrombosis by 10%, omeprazole should be avoided in patients taking warfarin (7). There is insufficient data on other PPIs.Limited data suggest that the serum levels of digoxin do not change in the concomitant use of this drug with pantoprazole or rabeprazole (8,9). Omeprazole increases the digoxin blood levels (10). There is no data about the other PPI. S68In the concomitant use of lansoprazole, omeprazole, and esomeprazole with acetylsalicylic acid (ASA), the effectiveness of ASA does not change (11-13). There is no data on the other PPI.It has been shown in studies that the concomitant use of pantoprazole or lansoprazole in patients using diazepam does not affect the metabolism of diazepam (14-16). The use of omeprazole or esomeprazole may increase the effect of diazepam (16,17).We were able to find only one study in the literature regarding the concomitant use of PPI and oral contraceptives in whic...

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Stereoselective Interaction of Omeprazole with Warfarin in Healthy Men

Cited by 114 publications

References 0 publications

Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics

Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics

Interactions of Warfarin

When proton pump inhibitors are compared, are there specific cases in which a certain proton pump inhibitors should be particularly preferred?

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