Phytonadione

Vitamin K/Drug Interactions:

  • GeneralGeneral: According to secondary sources, multiple drugs may cause complications when taken with menadiol sodium diphosphase, a form of vitamin K that is not used in the United States.
  • AntacidsAntacids: Based on the mechanism of action, high doses of antacids may decrease absorption of fat-soluble vitamins such as vitamin K. Clinical evidence is lacking.
  • AntibioticsAntibiotics: Vitamin K is synthesized by bacteria in the human gut. Since some antibiotics (such as broad-spectrum antibiotics) may decrease bacteria in the human gut, they may lower vitamin K levels and increase the risk of deficiency in people not ingesting adequate amounts. Clinical evidence is lacking.
  • Anticoagulants and antiplateletsAnticoagulants and antiplatelets: Vitamin K antagonists interfere with the synthesis of vitamin K-dependent clotting factors in the liver. Several medications, including warfarin, have been developed for venous thromboembolism (75). Vitamin K may decrease the blood-thinning effects of vitamin K antagonists and will therefore lower the PT or INR value, increasing the risk of clotting. Therefore, people taking warfarin are usually counseled to keep dietary vitamin K levels consistent and to avoid vitamin K supplements. Conversely, vitamin K is used to treat overdoses or excess anticoagulant effects of warfarin and to reverse the effects of warfarin prior to surgery or other procedures. Over-the-counter vitamin K1-containing multivitamin supplements decrease warfarin anticoagulation in vitamin K1-depleted patients. Vitamin K-depleted patients are sensitive to even small changes in vitamin K1 intake. In humans, oral or intravenous vitamin K were shown to decrease elevated PT or INRs associated with warfarin use (55; 56), but effects on induced coagulopathy are not clear (76). In humans, low-dose oral vitamin K (1.25mg) did not reduce bleeding in warfarin recipients with INRs of 4.5-10.0 (77). Results from a meta-analysis showed that polymorphism of the vitamin K epoxide reductase complex subunit 1 (VKORC1) played a role in the warfarin dosage requirement (78). According to the authors of reviews, manipulation of dietary vitamin K levels is an option for managing stability of oral anticoagulant therapy (79; 80). In human research, oral vitamin K was not shown to affect the pharmacokinetics of S- and R-warfarin (81).
  • AnticonvulsantsAnticonvulsants: For pregnant epileptic women taking anticonvulsants, the incidence of bleeding tendencies in the newborn was not increased (59). At this time, there is inadequate evidence in support of vitamin K during pregnancy in women with epilepsy (60). Vitamin K deficiency has been reported in patients treated with anticonvulsants and in infants of mothers taking anticonvulsants (82; 83; 84).
  • Antidiabetic agentsAntidiabetic agents: In epidemiological research, higher intakes of phylloquinone were associated with increased insulin sensitivity and glycemic status, but not fasting levels of insulin, glucose, or HbA1c (51).
  • Anti-inflammatory agentsAnti-inflammatory agents: In epidemiological research, vitamin K status was inversely associated with circulating inflammatory markers (85). In humans, vitamin K did not decrease levels of IL-6, osteoprotegerin, and C-reactive proteins (86).
  • AntilipemicsAntilipemics: Replacement of long-chain triglycerides with medium-chain triglycerides/long-chain triglyceride lipid emulsion resulted in a decrease in plasma vitamin K1 levels (87). However, in the Framingham Offspring Cohort, dietary phylloquinone was associated with lower triglyceride levels (54). Based on the mechanism of action, cholestyramine (Questran?) mineral oil may decrease the absorption of oral vitamin K and increase vitamin K requirements. Clinical evidence is lacking.
  • AntineoplasticsAntineoplastics: The relationship between dietary intake of vitamin K and the risk of cancer is of interest (88). In the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg), there was an inverse relationship between intake of menaquinones and prostate cancer (89). There was a lack of an association between the intake of phylloquinone and prostate cancer. In the same cohort, the dietary intake of menaquinones (determined by the consumption of cheese) was associated with a reduced risk of cancer incidence and fatality (90). At this time, the results from clinical studies are unclear regarding the effects vitamin K on hepatocellular carcinoma (91; 92; 93; 94).
  • Antiobesity agentsAntiobesity agents: In adult men and women, adipose phylloquinone was inversely associated with percent body fat (12).
  • Bone agentsBone agents: In humans, vitamin K supplements may increase bone mineral density and bone strength (95; 96; 50; 47; 46; 48; 49; 50). However, the majority of studies have been conducted on patients in Japan using an approved menatetrenone form of vitamin K. Epidemiological studies suggest that decreased vitamin K intake is associated with increased risk of hip fracture, but not decreased bone density (97; 98), although the association between low intakes of vitamin K and decreased bone density was seen in women in some studies (99; 100). In elderly patients with long-standing poststroke hemiplegia and hypovitaminosis D, serum vitamin K1 concentrations were decreased and related with decreased bone Gla protein levels (101). In elderly women with Alzheimer's disease, serum vitamin K1 levels were lower and related to the lower levels of Glu osteocalcin (102). In girls, intake of phylloquinone intake was not consistently associated with bone turnover markers or bone mineral content; however, better vitamin K status (plasma phylloquinone and low %ucOC) was associated with lower bone resorption and formation (103). Furthermore, plasma phylloquinone levels were inversely associated with biochemical endpoints, NTx and osteocalcin. In postmenopausal women, vitamin K intake was associated with reduced concentrations of pyridinoline crosslinks (100). In humans over a two-year period, although biochemical changes were observed with vitamin K2 alone, bone mineral density did not increase in the absence of bisphosphonates (104).
  • Cytochrome P450-modifying agentsCytochrome P450-modifying agents: In vitro, vitamin K2 was shown to dose-dependently activate and directly bind to the SXR receptor, which regulates drug clearance in the liver and intestine, and to induce expression of the SXR target gene, CYP3A4, in osteosarcoma cell lines (105).
  • DactinomycinDactinomycin: Based on the mechanism of action, dactinomycin, a cancer chemotherapy drug, may decrease the effects of vitamin K and increase vitamin K requirements. Clinical evidence is lacking.
  • Hormonal agentsHormonal agents: In perimenopausal women, concentrations of follicle-stimulating hormone (FSH) correlated with undercarboxylated osteocalcin levels, a marker for vitamin K status (106).
  • IsoniazidIsoniazid: Case reports exist of vitamin K deficiency in patients treated with rifampin and isoniazid (107; 108).
  • OrlistatOrlistat: Based on the mechanism of action, orlistat may decrease vitamin K absorption. Clinical evidence is lacking.
  • QuininesQuinines: Based on the mechanism of action, quinine, or quinidine, may increase vitamin K requirements. Clinical evidence is lacking.
  • RifampinRifampin: Case reports exist of vitamin K deficiency in patients treated with rifampin and isoniazid (107; 108).
  • SalicylatesSalicylates: In vitro, salicylates have been shown to antagonize vitamin K metabolism (109).
  • TiratricolTiratricol: Based on the mechanism of action, tiratricol (a drug not available in the United States) may decrease vitamin K absorption. Clinical evidence is lacking.
  • Vitamin AVitamin A: In animals, vitamin A was found to antagonize vitamin K (110).
  • Vitamin DVitamin D: Vitamin D, calcium, and vitamin K are commonly contained in vitamin/mineral supplements for bone health. In young girls, vitamin D supplementation was not found to affect vitamin K status (111).
  • Vitamin EVitamin E: In adults with normal coagulation status, vitamin E increased PIVKA-II (112).

    • Vitamin K/Herb/Supplement Interactions:

  • GeneralGeneral: According to secondary sources, multiple agents may cause complications when taken with menadiol sodium diphosphase, a form of vitamin K that is not used in the United States.
  • AntacidsAntacids: Based on the mechanism of action, high doses of antacids may decrease absorption of fat-soluble vitamins such as vitamin K. Clinical evidence is lacking.
  • AntibacterialsAntibacterials: Vitamin K is synthesized by bacteria in the human gut. Since some antibiotics (such as broad-spectrum antibiotics) may decrease bacteria in the human gut, they may lower vitamin K levels and increase the risk of deficiency in people not ingesting adequate amounts. Clinical evidence is lacking.
  • Anticoagulants and antiplateletsAnticoagulants and antiplatelets: Vitamin K antagonists interfere with the synthesis of vitamin K-dependent clotting factors in the liver, according to secondary sources. Several medications, including warfarin, have been developed for venous thromboembolism (75). Vitamin K may decrease the blood-thinning effects of vitamin K antagonists and will therefore lower the PT or INR value, increasing the risk of clotting. Therefore, people taking warfarin are usually counseled to keep dietary vitamin K levels consistent and to avoid vitamin K supplements. Conversely, vitamin K is used to treat overdoses or any excess anticoagulant effects of warfarin and to reverse the effects of warfarin prior to surgery or other procedures. Over-the-counter vitamin K1-containing multivitamin supplements decrease warfarin anticoagulation in vitamin K1-depleted patients. Vitamin K-depleted patients are sensitive to even small changes in vitamin K1 intake. In humans, oral or intravenous vitamin K were shown to decrease elevated PT or INRs associated with warfarin use (55; 56), but the effects on induced coagulopathy are not clear (76). In humans, low-dose oral vitamin K (1.25mg) did not reduce bleeding in warfarin recipients, with INRs of 4.5-10.0 (77). Results from a meta-analysis showed that polymorphism of the vitamin K epoxide reductase complex subunit 1 (VKORC1) played a role in the warfarin dosage requirement (78). According to the authors of reviews, manipulation of dietary vitamin K levels is an option for managing stability of oral anticoagulant therapy (79; 80). In human research, oral vitamin K was not shown to affect the pharmacokinetics of S- and R-warfarin (81).
  • AnticonvulsantsAnticonvulsants: For pregnant epileptic women taking anticonvulsants, the incidence of bleeding tendencies in the newborn was not increased (59). At this time, there is inadequate evidence in support of vitamin K during pregnancy in women with epilepsy (60). Vitamin K deficiency has been reported in patients treated with anticonvulsants and in infants of mothers taking anticonvulsants (82; 83; 84).
  • Anti-inflammatory herbs and supplementsAnti-inflammatory herbs and supplements: In epidemiological research, vitamin K status was inversely associated with circulating inflammatory markers (85). In humans, vitamin K did not decrease levels of IL-6, osteoprotegerin, and C-reactive proteins (86).
  • AntilipemicsAntilipemics: Replacement of long-chain triglycerides with medium-chain triglycerides/long-chain triglyceride lipid emulsion resulted in a decrease in plasma vitamin K1 levels (87). However, in the Framingham Offspring Cohort, dietary phylloquinone was associated with lower triglyceride levels (54). Based on the mechanism of action, cholestyramine (Questran?) mineral oil may decrease the absorption of oral vitamin K and increase vitamin K requirements. Clinical evidence is lacking.
  • AntineoplasticsAntineoplastics: The relationship between dietary intake of vitamin K and the risk of cancer is of interest (88). In the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg), there was an inverse relationship between intake of menaquinones and prostate cancer (89). There was a lack of an association between the intake of phylloquinone and prostate cancer. In the same cohort, the dietary intake of menaquinones (determined by the consumption of cheese) was associated with a reduced risk of cancer incidence and fatality (90). At this time, the results from clinical studies are unclear regarding the effects vitamin K on hepatocellular carcinoma (91; 92; 93; 94).
  • Antiobesity herbs and supplementsAntiobesity herbs and supplements: In adult men and women, adipose phylloquinone was inversely associated with percent body fat (12).
  • AntioxidantsAntioxidants: The role of vitamin K as an antioxidant has been discussed by some authors (113; 114). However, according to secondary sources, vitamin K may interfere with the function of glutathione.
  • Bone agentsBone agents: In humans, vitamin K supplements may increase bone mineral density and bone strength (95; 96; 50; 47; 46; 48; 49; 50). However, the majority of studies have been conducted on patients in Japan using an approved menatetrenone form of vitamin K. Epidemiological studies suggest that decreased vitamin K intake is associated with increased risk of hip fracture, but not decreased bone density (97; 98), although the association between low intakes of vitamin K and decreased bone density was seen in women in some studies (99; 100). In elderly patients with long-standing poststroke hemiplegia and hypovitaminosis D, serum vitamin K1 concentrations were decreased and related positively with bone Gla protein levels, which were also lower (101). In elderly women with Alzheimer's disease, serum vitamin K1 levels were lower and related to the lower levels of Glu osteocalcin (102). In girls, intake of phylloquinone intake was not consistently associated with bone turnover markers or bone mineral content; however, better vitamin K status (plasma phylloquinone and low %ucOC) was associated with lower bone resorption and formation (103). Furthermore, plasma phylloquinone levels were inversely associated with biochemical endpoints, NTx and osteocalcin. In postmenopausal women, vitamin K intake was associated with reduced concentrations of pyridinoline crosslinks (100). In humans over a two-year period, although biochemical changes were observed with vitamin K2 alone, bone mineral density did not increase in the absence of bisphosphonates (104).
  • Cytochrome P450-modifying agentsCytochrome P450-modifying agents: In vitro, vitamin K2 was shown to dose-dependently activate and directly bind to the SXR receptor, which regulates drug clearance in the liver and intestine, and to induce expression of the SXR target gene, CYP3A4, in osteosarcoma cell lines (105).
  • Hormonal agentsHormonal agents: In perimenopausal women, concentrations of follicle-stimulating hormone (FSH) correlated with undercarboxylated osteocalcin levels, a marker for vitamin K status (106).
  • HypoglycemicsHypoglycemics: In epidemiological research, higher intakes of phylloquinone were associated with increased insulin sensitivity and glycemic status, but not fasting levels of insulin, glucose, or HbA1c (51).
  • SalicylatesSalicylates: In vitro, salicylates have been shown to antagonize vitamin K metabolism (109).
  • Vitamin AVitamin A: In animals, vitamin A was found to antagonize vitamin K (110).
  • Vitamin DVitamin D: Vitamin D, calcium, and vitamin K are commonly contained in vitamin/mineral supplements for bone health. In young girls, vitamin D supplementation was not found to affect vitamin K status (111).
  • Vitamin EVitamin E: In adults with normal coagulation status, vitamin E increased PIVKA-II (112).

    • Vitamin K/Food Interactions:

  • ButterButter: The effect of food composition on vitamin K absorption in human volunteers was investigated (115). Consumption of spinach with butter increased circulating phylloquinone levels and menaquinone-4.
  • Dietary triglyceridesDietary triglycerides: Replacement of long-chain triglycerides with medium-chain triglycerides/long-chain triglyceride lipid emulsion resulted in a decrease in plasma vitamin K1 levels (87). However, in the Framingham Offspring Cohort, dietary phylloquinone was associated with lower triglyceride levels (54).
  • MilkMilk: In postmenopausal women, the addition of vitamin K to a fortified milk supplement did not alter changes in bone turnover rates induced by the milk supplement alone (116).
  • SpinachSpinach: The effect of food composition on vitamin K absorption in human volunteers was investigated (115). Circulating phylloquinone levels after spinach were increased.

    • Vitamin K/Lab Interactions:

  • Blood glucoseBlood glucose: In epidemiological research, higher intakes of phylloquinone were associated with increased insulin sensitivity and glycemic status, but not fasting levels of insulin, glucose, or HbA1c (51).
  • Body weightBody weight: In adult men and women, adipose phylloquinone was inversely associated with percent body fat (12).
  • Coagulation panelCoagulation panel: In newborns, maternal antenatal administration of phylloquinone increased activities of vitamin K-dependent coagulation factors in umbilical blood (117). In humans, vitamin K decreased the INR (118).
  • Hormone panelHormone panel: In perimenopausal women, concentrations of follicle-stimulating hormone (FSH) correlated with undercarboxylated osteocalcin levels, a marker for vitamin K status (106).
  • Inflammatory markersInflammatory markers: In epidemiological research, vitamin K status was inversely associated with circulating inflammatory markers (85). In humans, vitamin K did not decrease levels of IL-6, osteoprotegerin, and C-reactive proteins (86).
  • Lipid levelsLipid levels: In humans, phylloquinone increased plasma triglycerides and decreased HDL cholesterol (53). However, in the Framingham Offspring Cohort, dietary phylloquinone was associated with lower triglyceride levels (54).
  • Liver enzymesLiver enzymes: In vitro, vitamin K2 was shown to dose-dependently activate and directly bind to the SXR receptor, which regulates drug clearance in the liver and intestine, and to induce expression of the SXR target gene, CYP3A4, in osteosarcoma cell lines (105).
  • Markers of bone formation and resorptionMarkers of bone formation and resorption: In humans, markers of bone turnover have been shown to be affected by dietary restriction and repletion of vitamin K (119). Increased dietary phylloquinone increased serum gamma-carboxylated osteocalcin; under-gamma-carboxylated osteocalcin levels were decreased (29; 120; 121; 122; 123; 124; 125; 25; 126).