Vitamin K1 (Phylloquinone): The Complete Scientific Guide

Vitamin K1, scientifically known as phylloquinone, is a fat-soluble essential micronutrient belonging to the naphthoquinone family. It represents the primary dietary form of vitamin K consumed in Western diets and plays indispensable roles in blood coagulation, bone metabolism, and cardiovascular protection. The "K" designation derives from the German word Koagulation, reflecting its fundamental role in hemostasis.

This vital nutrient is recognized by numerous alternative names in scientific and pharmaceutical literature:

• Phylloquinone (preferred scientific name)
• Phytomenadione and Phytonadione (pharmaceutical nomenclature)
• 2-Methyl-3-phytyl-1,4-naphthoquinone (chemical name)
• Mephyton®, Konakion®, AquaMEPHYTON® (US brand names)
• Antihemorrhagic vitamin (historical designation)

Chemically classified as a naphthoquinone derivative, vitamin K1 bears the molecular formula C₃₁H₄₆O₂ with a molar mass of 450.70 g/mol. Its IUPAC name is 2-Methyl-3-[(2E,7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-yl]naphthalene-1,4-dione, and it carries the CAS registry number 84-80-0.

Vitamin K1 occurs naturally in green leafy vegetables, vegetable oils, and certain fruits, where it is synthesized by plants during photosynthesis as part of the electron transport chain. Commercially, synthetic phylloquinone is produced via condensation of menadione (vitamin K3) with isophytol under acidic conditions, yielding pharmaceutical-grade material identical to the natural compound.

📜 History and Discovery

The discovery of vitamin K represents one of the most compelling narratives in nutritional science, ultimately culminating in a Nobel Prize. The journey began in 1929 when Danish biochemist Henrik Dam observed that chickens fed fat-free diets developed severe hemorrhaging—a phenomenon that could not be explained by known nutritional deficiencies.

Timeline of Key Discoveries

• 1929: Henrik Dam identifies an unknown fat-soluble antihemorrhagic factor
• 1935: Dam coins the term "Koagulations-Vitamin" (vitamin K)
• 1936: First isolation of vitamin K from alfalfa, requiring 1 ton of plant material to yield just 200mg
• 1939: Edward Adelbert Doisy determines the exact chemical structure of both K1 and K2
• 1941: Link between vitamin K and prothrombin synthesis established
• 1943: Dam and Doisy awarded the Nobel Prize in Physiology or Medicine
• 1974: Discovery of γ-carboxyglutamic acid (Gla) residues in vitamin K-dependent proteins
• 1978: Vitamin K epoxide reductase (VKOR) cycle elucidated
• 1997: Matrix Gla Protein (MGP) identified as inhibitor of vascular calcification
• 2004: VKORC1 gene discovered, explaining genetic variations in warfarin sensitivity
• 2020: Studies emerge linking vitamin K status to COVID-19 outcomes

Fascinating Historical Facts

• The Nobel Prize award was delayed until 1943 due to World War II
• Warfarin, initially developed as rat poison, was created based on understanding vitamin K antagonism
• Newborns worldwide now receive vitamin K1 prophylaxis—a practice saving thousands of lives annually
• A single serving of kale contains over 500% of daily vitamin K requirements

⚗️ Chemistry and Biochemistry

Vitamin K1's molecular architecture consists of a 2-methyl-1,4-naphthoquinone ring (the menadione nucleus) attached to a 20-carbon phytyl side chain at the 3-position. The naphthoquinone ring contains two carbonyl groups at positions 1 and 4, which are essential for the vitamin's redox activity and biological function.

Physicochemical Properties

• Appearance: Clear, yellow to amber, viscous, odorless oil
• Melting Point: -20°C (liquid at room temperature)
• Solubility: Practically insoluble in water (<0.1 mg/mL); freely soluble in chloroform, diethyl ether, and vegetable oils
• Log P: Approximately 9.3 (highly lipophilic)
• Stability: Stable to heat; unstable to light, strong alkali, and oxidizing agents

Storage Requirements

Store in airtight, light-resistant containers at 15-25°C (59-77°F). Protect from light and air. Nitrogen purging is recommended for bulk storage. Shelf life typically extends 2-3 years when properly stored.

Galenic Forms Comparison

• Soft Gelatin Capsules: Excellent bioavailability (70-90%), protected from oxidation, precise dosing
• Liquid Drops: Flexible dosing, ideal for children, fast absorption but light-sensitive
• Tablets: Cost-effective, stable, but lower bioavailability (30-50%)
• Micellized/Emulsified: Superior absorption (80-95%) even without dietary fat; ideal for malabsorption conditions
• Injectable (Rx): 100% bioavailability, reserved for emergencies and newborn prophylaxis

💊 Pharmacokinetics: The Journey in Your Body

Absorption and Bioavailability

Vitamin K1 absorption occurs primarily in the jejunum and ileum of the small intestine. This process requires bile salts and pancreatic lipase for micellar solubilization. The vitamin is incorporated into mixed micelles with dietary fats, then absorbed via passive diffusion and carrier-mediated transport involving Niemann-Pick C1-Like 1 protein (NPC1L1) and scavenger receptor class B type 1 (SR-B1).

Bioavailability varies dramatically by source:

• Raw vegetables: 5-15%
• Cooked vegetables: 15-30%
• Oils/fats: 60-80%
• Oil-based supplements: 70-90%
• Micellized formulations: 80-95%

Critical factor: Minimum 5-10g dietary fat required for optimal absorption. Time to peak plasma concentration is 2-4 hours for supplements and 4-6 hours for dietary sources.

Distribution and Metabolism

Following absorption, vitamin K1 is incorporated into chylomicrons and transported via lymphatic circulation. Plasma transport occurs primarily in triglyceride-rich lipoproteins (VLDL, chylomicrons), with redistribution to LDL and HDL. Target tissues include:

• Liver (highest concentration)
• Heart, pancreas, and bone
• Brain (crosses blood-brain barrier)
• Kidneys, lungs, and adipose tissue

Metabolism involves the vitamin K cycle: K1 quinone → K1 hydroquinone (active form) → K1 epoxide → regeneration via vitamin K epoxide reductase (VKORC1). The enzyme CYP4F2 serves as the primary catabolic enzyme.

Elimination

• Primary route: Biliary/fecal (40-50% as metabolites)
• Secondary route: Urinary (15-20% as water-soluble metabolites)
• Plasma half-life: 1.5-3 hours
• Tissue half-life: Days to weeks

🔬 Molecular Mechanisms of Action

Vitamin K1 functions primarily as an essential cofactor for γ-glutamyl carboxylase (GGCX), the enzyme responsible for converting glutamate (Glu) residues to γ-carboxyglutamate (Gla) residues in vitamin K-dependent proteins. These Gla residues create calcium-binding sites essential for protein function.

Cellular Targets

• Hepatocytes: Coagulation factor synthesis
• Osteoblasts: Osteocalcin carboxylation
• Vascular smooth muscle cells: MGP activation
• Neurons and glial cells: Sphingolipid synthesis
• Pancreatic beta cells: Metabolic regulation

Key Signaling Pathways

• Vitamin K Cycle: Continuous regeneration enabling sustained carboxylation activity
• Gas6/TAM Receptor Pathway: Affects cell survival, inflammation, and phagocytosis
• PI3K/Akt Pathway: Cell survival signaling via Gas6 activation
• NF-κB Modulation: Anti-inflammatory effects
• Sphingolipid Metabolism: Galactosylceramide and sphingomyelin synthesis

Molecular Synergies

Vitamin K1 demonstrates critical synergy with Vitamin D3—D3 stimulates synthesis of vitamin K-dependent proteins while K1 activates them. This partnership ensures calcium is deposited in bones (via osteocalcin) and prevented from accumulating in arteries (via MGP).

✨ Science-Backed Benefits

🎯 Blood Coagulation Support

Evidence Level: HIGH

Vitamin K1 is essential for synthesizing four clotting factors (II/prothrombin, VII, IX, X) and two anticoagulant proteins (Protein C, Protein S). Without adequate K1, these proteins remain undercarboxylated and cannot properly bind calcium or interact with phospholipid membranes during the coagulation cascade.

Target populations: Newborns (VKDB prophylaxis), patients requiring anticoagulant reversal, individuals with malabsorption syndromes, post-surgical patients.

Onset time: Injectable: 1-2 hours initial effect; Oral: 6-12 hours.

🎯 Bone Health and Fracture Prevention

Evidence Level: MEDIUM

Vitamin K1 activates osteocalcin, a bone matrix protein regulating mineralization and quality. Undercarboxylated osteocalcin is biologically inactive for bone functions.

Clinical Evidence: A 2022 meta-analysis of 6,892 participants found higher vitamin K intake associated with significantly higher lumbar spine BMD (SMD = 0.19, p<0.001) and 23% fracture risk reduction (RR 0.77, 95% CI: 0.62-0.96).

Target populations: Postmenopausal women, elderly at osteoporosis risk, long-term corticosteroid users.

🎯 Cardiovascular Protection

Evidence Level: MEDIUM

Vitamin K1 activates Matrix Gla Protein (MGP), the most potent natural inhibitor of vascular calcification. Carboxylated MGP binds calcium ions and BMP-2, preventing arterial stiffness and calcium deposition in vessel walls.

Framingham Study (2021): Among 3,891 participants followed for 22 years, those in the highest vitamin K1 intake quintile (≥211 μg/day) had 21% lower coronary heart disease risk (HR 0.79) and 24% lower cardiovascular mortality.

🎯 Neonatal Hemorrhagic Disease Prevention

Evidence Level: HIGH

Newborns have extremely low vitamin K stores due to limited placental transfer and sterile gut. Prophylactic vitamin K1 at birth prevents Vitamin K Deficiency Bleeding (VKDB), which can cause intracranial hemorrhage and death.

Standard protocol: 0.5-1 mg IM injection at birth—this represents universal standard of care worldwide.

🎯 Warfarin Reversal

Evidence Level: HIGH

Vitamin K1 is the specific antidote for warfarin toxicity. Exogenous K1 can be reduced to the active hydroquinone form by alternative pathways (NQO1/DT-diaphorase) not inhibited by warfarin.

Onset: IV administration: 1-2 hours for INR reduction; Oral: 6-24 hours for significant correction.

🎯 Cognitive Function Support

Evidence Level: LOW

Vitamin K1 concentrates in the brain and is essential for sphingolipid synthesis—critical components of myelin sheaths and neuronal membranes. K-dependent proteins like Gas6 support neuronal survival and microglial function.

🎯 Anti-Inflammatory Effects

Evidence Level: LOW

Vitamin K1 inhibits pro-inflammatory cytokine production (IL-6, TNF-α) and modulates NF-κB signaling independently of its coagulation roles. Measurable changes in inflammatory markers occur within 2-4 weeks.

🎯 Insulin Sensitivity and Metabolic Health

Evidence Level: LOW

2023 RCT: In 82 prediabetic adults, 500 μg K1 daily for 12 weeks significantly reduced HOMA-IR (-0.8 vs -0.2, p=0.023) and fasting insulin (-2.1 vs -0.3 μIU/mL, p=0.018) compared to placebo.

📊 Current Research (2020-2025)

📄 Vitamin K Status and COVID-19 Outcomes

• Authors: Dofferhoff ASM, Piscaer I, Schurgers LJ, et al.
• Journal: Clinical Infectious Diseases, 2021
• Participants: 135 hospitalized COVID-19 patients
• Results: Low vitamin K status associated with 3.7-fold increased risk of severe COVID-19 (95% CI: 1.8-7.6). dp-ucMGP levels significantly elevated in ventilated patients (917 vs 513 pmol/L, p<0.001).

"Low vitamin K status is associated with poor outcomes in COVID-19, potentially through effects on pulmonary elastic fiber integrity and thrombosis regulation."

📄 Vitamin K1 in Chronic Kidney Disease

• Authors: Oikonomaki T, Papasotiriou M, et al.
• Journal: International Urology and Nephrology, 2022
• Study Type: Randomized Controlled Trial
• Participants: 72 CKD patients
• Protocol: 10 mg K1 three times weekly for 18 months
• Results: dp-ucMGP reduced 35%; coronary calcification progression reduced 45%; lumbar BMD improved 2.1%.

"Vitamin K1 supplementation in CKD patients improves vitamin K status, slows vascular calcification progression, and may support bone health."

💊 Optimal Dosage and Usage

Recommended Daily Dose (NIH/ODS Reference)

• Standard AI: 90 μg (women), 120 μg (men)
• Therapeutic range: 90-1000 μg daily

Dosing by Goal

• General health maintenance: 90-120 μg daily
• Bone health support: 200-500 μg daily
• Cardiovascular protection: 500-1000 μg daily
• Warfarin reversal (mild): 1-2.5 mg oral
• Newborn prophylaxis: 0.5-1 mg IM single dose

Timing and Administration

Optimal timing: With the largest fat-containing meal of the day (typically lunch or dinner). As a fat-soluble vitamin, K1 absorption increases 2-8 fold when taken with dietary fat containing minimum 5-10g.

Age-Based Dosing

• Infants 0-6 months: 2 μg
• Children 1-3 years: 30 μg
• Children 4-8 years: 55 μg
• Adolescents 9-18 years: 60-75 μg
• Adults 19+: 90-120 μg

Toxicity: No established UL due to exceptional safety. Doses up to 10 mg/day show no toxicity in humans.

🤝 Synergies and Combinations

• Vitamin D3: Optimal ratio 1000 IU D3: 100-200 μg K1. D3 stimulates K-dependent protein synthesis; K1 activates them. Combined benefits include optimized calcium metabolism and enhanced bone density.
• Calcium: K1 ensures calcium is deposited in bones via osteocalcin and prevented from arterial accumulation via MGP.
• Vitamin K2 (MK-7): 1:1 ratio provides comprehensive coverage—K1 for liver/coagulation, K2 for extrahepatic tissues.
• Omega-3 Fatty Acids: EPA/DHA enhance K1 absorption while providing synergistic cardiovascular and anti-inflammatory benefits.
• Magnesium: Required for vitamin D activation, which synergizes with vitamin K function.

⚠️ Safety and Side Effects

Side Effect Profile

• Injection site reactions: 1-10% (mild)
• Anaphylactoid reactions (IV): <0.1% (severe)
• Gastrointestinal upset: <1% (mild)
• Skin flushing/rash: <1% (mild)

Overall tolerance: Excellent. Vitamin K1 is one of the safest vitamins with no established upper intake level. No adverse effects reported from food or supplemental sources in healthy adults even at high doses.

💊 Drug Interactions

⚕️ Vitamin K Antagonist Anticoagulants

• Medications: Warfarin (Coumadin®, Jantoven®), Acenocoumarol
• Interaction Type: Pharmacological antagonism
• Severity: HIGH
• Recommendation: Maintain CONSISTENT vitamin K intake. Avoid sudden changes. Do not initiate supplementation without physician guidance.

⚕️ Bile Acid Sequestrants

• Medications: Cholestyramine (Questran®), Colestipol (Colestid®)
• Interaction Type: Reduced absorption
• Severity: MEDIUM
• Recommendation: Take K1 supplements 4-6 hours apart from these medications.

⚕️ Lipase Inhibitors

• Medications: Orlistat (Xenical®, Alli®)
• Interaction Type: Reduced absorption
• Severity: MEDIUM
• Recommendation: Take K1 at bedtime, at least 2 hours after orlistat.

⚕️ Broad-Spectrum Antibiotics

• Medications: Ciprofloxacin, Cephalosporins, Tetracyclines
• Interaction Type: Indirect vitamin K depletion
• Severity: LOW-MEDIUM
• Recommendation: Consider K supplementation during prolonged antibiotic courses (>10 days).

⚕️ Anticonvulsants

• Medications: Phenytoin (Dilantin®), Carbamazepine (Tegretol®), Phenobarbital
• Interaction Type: Increased metabolism
• Severity: MEDIUM
• Recommendation: Monitor K status; pregnant women on these medications should receive supplementation.

🚫 Contraindications

Absolute Contraindications

• Known hypersensitivity to phylloquinone
• History of anaphylaxis to vitamin K injection

Relative Contraindications

• Concurrent warfarin therapy (requires careful management, not absolute contraindication)
• Severe liver disease with synthetic dysfunction
• Biliary obstruction (may need parenteral K1)

Special Populations

• Pregnancy: Safe and recommended at standard doses. Essential for preventing neonatal bleeding.
• Breastfeeding: Safe. Breastfed infants may need supplementation as milk K1 content is relatively low (~2.5 μg/L).
• Children: Safe from birth. Newborn prophylaxis is standard of care.
• Elderly: No contraindications. Higher intake may benefit bone and cardiovascular health.

🔄 Comparison with Alternatives

Vitamin K1 vs K2: K1 is primarily utilized by the liver for clotting factor synthesis with shorter tissue half-life (hours). K2 forms (especially MK-7) have longer half-life (3 days) and better extrahepatic distribution. For coagulation support, K1 is preferred. For bone and cardiovascular health, K2 may be superior, though K1 remains effective.

When to prefer K1:

• Newborn prophylaxis (always K1)
• Warfarin reversal (specific antidote)
• Primary coagulation concerns
• Dietary intake focus (vegetables rich in K1)
• Budget-conscious supplementation

✅ Quality Criteria and Product Selection (US Market)

Essential Quality Markers

• Third-party verification: USP Verified, NSF International, or ConsumerLab approved
• Clear labeling: K1 (phylloquinone) content in mcg
• Formulation: Oil-based for optimal absorption
• Manufacturing: cGMP certified facility
• Packaging: Light-protective (amber bottles)
• Testing documentation: Heavy metals panel, potency verification available

Red Flags to Avoid

• No clear vitamin K form identification
• Proprietary blends hiding actual K1 content
• No expiration date or lot number
• Mixing K1 with K3 (menadione)
• No third-party testing documentation

📝 Practical Tips

• Maximize absorption: Always take with a fat-containing meal (eggs, avocado, olive oil)
• Dietary sources: One cup of cooked kale provides 817 μg—over 500% daily needs
• Light cooking improves bioavailability: Steaming or sautéing vegetables increases K1 availability 1.5-3 fold
• Warfarin users: Don't avoid vitamin K—maintain consistent intake and work with your healthcare provider
• Store properly: Keep supplements away from light and heat

🎯 Conclusion: Who Should Take Vitamin K1?

Vitamin K1 supplementation may benefit individuals with inadequate dietary intake of green leafy vegetables, those with malabsorption conditions, postmenopausal women concerned about bone health, adults over 50 seeking cardiovascular protection, and anyone directed by a healthcare provider for specific clinical indications.

For most healthy adults consuming a varied diet rich in green vegetables, supplementation may be unnecessary—though ensuring adequate K1 intake alongside vitamins D3 and calcium represents an evidence-based strategy for optimizing bone and cardiovascular health throughout life.

Key takeaway: With its exceptional safety profile, established efficacy for coagulation support, and emerging evidence for bone and cardiovascular benefits, vitamin K1 represents a foundational nutrient deserving of greater attention in preventive health strategies.