Differential effect of the enantiomers of phenprocoumon and warfarin on the vitamin K1-epoxide/vitamin K1 ratio in rat plasma

Schmidt, W.; Beermann, D.; Oesch, Franz; Jähnchen, E.

doi:10.1111/j.2042-7158.1979.tb13567.x

Cited by 13 publications

(5 citation statements)

References 16 publications

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“…No or only traces of vitamin K1-epoxide were detected in the plasma following injection of vitamin K1. This is also in agreement with results obtained in animals (Park et al, 1979;Schmidt et al, 1979;Trenk et al, 1980;Carlisle & Blaschke, 1981) and in man (Shearer et al, 1977;Bjomssen et al, 1979) following administration of tracer amounts of radiolabelled vitamin K1. The lack of accumulation of vitamin Kl-epoxide, after administration of vitamin Kl, is most likely associated with its more rapid conversion to vitamin K1, than the reverse reaction.…”

Section: Discussionsupporting

confidence: 92%

Cyclic interconversion of vitamin K1 and vitamin K1 2,3‐epoxide in man.

Bechtold¹,

Trenk²,

Meinertz³

et al. 1983

Brit J Clinical Pharma

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The disposition of a single intravenous bolus dose of 10 mg vitamin K1 and vitamin K1‐2,3‐epoxide were studied in two healthy subjects without and with 12 h pretreatment dose of phenprocoumon (0.4 mg/kg). For each compound administered alone the plasma concentration‐time profile was adequately fitted by a biexponential equation, with an average terminal half‐life of 2.0 and 1.15 h for the administered vitamin K and its 2,3‐ epoxide respectively. While vitamin K1 was measurable in plasma following administration of vitamin K1‐2,3‐epoxide, the epoxide was not detectable following administration of vitamin K1. Following pretreatment with phenprocoumon and after intravenous administration of vitamin K1, both the average half‐life and area under the plasma concentration‐time profile of vitamin K1 were marginally reduced to 1.5 h and 1.76 mg l‐1 h respectively, while the plasma concentration of vitamin K1‐2,3‐epoxide was readily measurable and its half‐life markedly prolonged to 14.7 h. Following pretreatment with phenprocoumon and after oral administration of vitamin K1‐2,3‐epoxide, no vitamin K1 was detectable in plasma and the half‐life of the epoxide was 13.8 h. Based on area considerations the data suggest that either phenprocoumon does more than just inhibit the reduction of vitamin K1‐2,3‐epoxide to vitamin K1, or that the simple model describing the interconversion between vitamin K1 and its epoxide is inadequate. The same conclusion is drawn from the analysis of comparable data in dogs, obtained by Carlisle & Blaschke (1981).

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Section: Discussionsupporting

confidence: 92%

Cyclic interconversion of vitamin K1 and vitamin K1 2,3‐epoxide in man.

Bechtold¹,

Trenk²,

Meinertz³

et al. 1983

Brit J Clinical Pharma

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“…If the anticoagulant activity of 4-hydroxycoumarins is related to the inhibition of epoxide reductase, then one might expect a greater accumulation of vitamin K1 2,3-epoxide with S warfarin. While this has been demonstrated in rats (Schmidt et al, 1979;Bell & Ren, 1981), previous studies in man have failed to show any difference in epoxide formation between the two enantiomers (Shearer et al, 1977;Choonara et al, 1986). However, the doses used (50 and 15 mg respectively) may have exceeded that required for maximum accumulation of epoxide.…”

Section: Discussionmentioning

confidence: 81%

“…Previous studies in man, involving single doses of the enantiomers of warfarin, have resulted in similar levels of vitamin K1 2,3-epoxide after both R and S warfarin following either physiological or pharmacological doses of vitamin K1 (Shearer et al, 1977;Choonara et al, 1986). A stereoselective difference in coumarin-induced vitamin K1 2,3-epoxide formation has however been demonstrated in rats (Schmidt et al, 1979;Bell & Ren, 1981 Venous blood samples were collected prior to the warfarin and at 0,0.5, 1,2,3,4,6,8,12,24,48 and 72 h after the vitamin K1. The warfarin capsules were prepared by the addition of lactose to the warfarin prior to packing gelatin capsules.…”

Section: Introductionmentioning

confidence: 93%

“…Previous studies in man, involving single doses of the enantiomers of warfarin, have resulted in similar levels of vitamin K1 2,3-epoxide after both R and S warfarin following either physiological or pharmacological doses of vitamin K1 (Shearer et al, 1977;Choonara et al, 1986). A stereoselective difference in coumarin-induced vitamin K1 2,3-epoxide formation has however been demonstrated in rats (Schmidt et al, 1979;Bell & Ren, 1981). The studies in man involved large doses of warfarin and it is possible that by the use of lower doses and also by achieving steady state concentrations, that a stereoselective effect on vitamin K1 metabolism may be demonstrated.…”

Section: Introductionmentioning

confidence: 99%

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Enantiomers of warfarin and vitamin K1 metabolism.

Choonara¹,

Haynes²,

Cholerton³

et al. 1986

Brit J Clinical Pharma

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The effect of the individual enantiomers of warfarin at steady state (lmg daily) was investigated in five healthy volunteers. Both enantiomers produced a significant increase in prothrombin time, but the increase with S warfarin (1.8 ± 0.8 s, mean ± s.d.) was greater than with R warfarin (1.0 ± 0.3 s), despite lower steady state plasma concentrations of S warfarin, due to its more rapid clearance. Following the administration of vitamin K1, the maximum plasma concentration and area under the plasma concentration time curve values for the metabolite vitamin K1 2,3-epoxide were greater after S warfarin than after R warfarin. The greater anticoagulant potency of S warfarin is reflected by a greater degree of inhibition of vitamin K1 epoxide reductase.

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“…VKORC1 is partly responsible for the recycling of vitamin K: when the VKOR activity is impaired by AR, it can be assumed that it has an impact on the concentrations of those vitamers, with a possible shift between epoxide forms and quinone forms. A dose-response relationship was suggested between ratio of epoxide and quinone forms of vitamin K1 in plasma and concentrations of two AR, phenprocoumon and warfarin (200). It was also proposed to used measurements of this ratio for diagnosis of AR intoxication in dogs (201).…”

Section: Vkor Activitymentioning

confidence: 99%

Biomarkers Potency to Monitor Non-target Fauna Poisoning by Anticoagulant Rodenticides

et al. 2020

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The widespread use of pesticides to control agricultural pests is a hot topic on the public scene of environmental health. Selective pest control for minimum environmental impact is a major goal of the environmental toxicology field, notably to avoid unintended poisoning in different organisms. Anticoagulant rodenticides cause abnormal blood coagulation process; they have been widely used to control rodents, allowing inadvertent primary and secondary exposure in domestic animals and non-target predatory wildlife species through direct ingestion of rodenticide-containing bait or by consumption of poisoned prey. To report toxic effect, the most common approach is the measurement of liver or plasma residues of anticoagulant rodenticides in dead or intoxicated animals showing clinical symptoms. However, one major challenge is that literature currently lacks a hepatic or plasma concentration threshold value for the differentiation of exposure from toxicity. Regarding the variation in pharmacology properties of anticoagulant rodenticides inter- and intra-species, the dose-response relationship must be defined for each species to prejudge the relative risk of poisoning. Beyond that, biomarkers are a key solution widely used for ecological risk assessment of contaminants. Since anticoagulant rodenticides (AR) have toxic effects at the biochemical level, biomarkers can serve as indicators of toxic exposure. In this sense, toxicological knowledge of anticoagulant rodenticides within organisms is an important tool for defining sensitive, specific, and suitable biomarkers. In this review, we provide an overview of the toxicodynamic and toxicokinetic parameters of anticoagulant rodenticides in different animal species. We examine different types of biomarkers used to characterize and differentiate the exposure and toxic effects of anticoagulant rodenticide, showing the strengths and weaknesses of the assays. Finally, we describe possible new biomarkers and highlight their capabilities.

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Differential effect of the enantiomers of phenprocoumon and warfarin on the vitamin K1-epoxide/vitamin K1 ratio in rat plasma

Cited by 13 publications

References 16 publications

Cyclic interconversion of vitamin K1 and vitamin K1 2,3‐epoxide in man.

Cyclic interconversion of vitamin K1 and vitamin K1 2,3‐epoxide in man.

Enantiomers of warfarin and vitamin K1 metabolism.

Biomarkers Potency to Monitor Non-target Fauna Poisoning by Anticoagulant Rodenticides

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