Phosphocreatine

Other Names

(N-Methyl-N′-phosphonocarbamimidamido)acetic acid2-[methyl-[(E)-N′-phosphonocarbamimidoyl]amino]acetic acidCPCreatine phosphateCreatine phosphoric acidCreatine-PCreatinefosfaatCreatinephosphoric acidCreatinfosfatoFosfato de creatinaFosfocreatinaFosfokreatiiniFosfokreatinFosfokreatynaGlycine, N-[imino(phosphonoamino)methyl]-N-methyl-Kreatin-fosfatKreatin-foszfátKreatinfosfátKreatinfosfat kislotaKreатинфосфорна кислотаKreатинфосфорная кислотаN-(Phosphonoamidino)sarcosineN-Methyl-N-(N-phosphonocarbamimidoyl)glycineN-Methyl-N-(phosphonocarbamimidoyl)glycineN-PhosphocreatinePCrPhosphagenPhosphocréatinePhosphorylcreatine[[Imino(phosphonoamino)methyl](methyl)amino]acetic acidفسفوکراتینفوسفات الكرياتينクレアチンリン酸磷酸肌酸크레아틴 인산

Synopsis

Phosphocreatine (Creatine Phosphate): A Comprehensive Reference

1. Identity, Chemical Characterization, and Natural Sources

1.1 Nomenclature and Chemical Identity

Phosphocreatine (abbreviated PCr or PC), also known as creatine phosphate (CP), is the phosphorylated form of endogenous creatine that serves as a rapidly mobilizable reserve of high-energy phosphates in skeletal muscle and the brain of vertebrates. The term "phosphocreatine" commonly refers to N-Methyl-N-(phosphono-carbamimidoyl)glycine having a chemical formulation of C₄H₁₀N₃O₅P, a molar mass of 211.11 g/mol, and a CAS Registry No. 67-07-2; it is also referred to in abbreviated form as PCr.

Phosphocreatine, which is also known as creatine phosphate, is a compound constructed of carbon, hydrogen, nitrogen, oxygen, and phosphorus, in the molecular structure C₄H₁₀N₃O₅P. The FDA Substance Registration System lists multiple pharmaceutical-grade salt forms of phosphocreatine, including phosphocreatine calcium tetrahydrate, phosphocreatine dipotassium, phosphocreatine magnesium, and phosphocreatine disodium tetrahydrate — all recognized as active forms sharing phosphocreatine as the active moiety.

1.2 Biosynthetic Origin and Natural Occurrence

Creatine is a nitrogenous organic acid, derived from glycine, L-arginine, and S-adenosyl-L-methionine, which is involved in energy transfer in the form of phosphocreatine (PCr) and which is metabolized to creatinine to be excreted by the kidney.

The biosynthesis of phosphocreatine in the body involves a multi-organ, multi-step pathway. In the kidneys, the enzyme AGAT catalyzes the conversion of two amino acids—arginine and glycine—into guanidinoacetate (also called glycocyamine or GAA), which is then transported in the blood to the liver, where a methyl group is added to GAA from the amino acid methionine by the enzyme GAMT, forming non-phosphorylated creatine. Phosphorylation by creatine kinase (ATP is required) then converts creatine to phosphocreatine (in muscle); catabolism proceeds by dehydration to form the cyclic Schiff base creatinine.

The mammalian body derives about half of its creatine stores from meat sources in food; the other half is made in the kidney and liver. About 50% of the daily requirement of creatine is obtained by endogenous synthesis in the body, mainly in kidney and liver; the remainder comes from nutrition, principally fish and meat. Approximately 2 g of creatine is lost from the body per day per 70 kg body weight, and this creatine is replaced either by endogenous synthesis or by absorption from the diet; creatine is obtained in the diet mainly from meat and dairy products.

Phosphocreatine is formed naturally within the body, with over 95% of the compound stored within the muscle cells. Phosphocreatine acts as an intracellular buffer for ATP and the "energy shuttle," which allows high-speed transport of macroergs from mitochondria to places of energy use. Creatine in high concentrations is found in tissues with significant energy consumption, such as skeletal muscle and the brain, while patients with mitochondrial encephalopathies may experience a decrease in creatine levels in the brain.

In vertebrate tissues, the only phosphagen is phosphocreatine (PC), and the corresponding phosphotransferase is creatine phosphokinase (CPK). Among invertebrates, a variety of phosphotransferase reactions are found in addition to CPK, including arginine phosphokinase (APK), glycocyamine phosphokinase (GPK), taurocyamine phosphokinase (TPK), and lombricine phosphokinase (LPK).

1.3 Pharmaceutical and Supplement Forms

As a pharmaceutical agent, phosphocreatine is administered primarily by injection. Phosphocreatine as such or in the form of its alkali metal salts has found pharmacological and therapeutical use in pathologic conditions of striated musculature, such as muscular atrophy and dystrophy, and also of heart musculature, such as myocardiosclerosis, degenerative myocardiopathies, and anoxies — conditions in which the myocardial contractility must be restored as quickly as possible. The most commonly used pharmaceutical form for intravenous and intraoperative applications is the disodium salt (phosphocreatine disodium tetrahydrate), which is soluble in aqueous solution.

Orally, phosphocreatine itself is not the conventional dietary supplement form. A study comparing the effect of creatine monohydrate and creatine phosphate supplementation on strength, body composition, and blood pressure over a 6-week period concludes that oral creatine phosphate supplementation may be as effective as creatine monohydrate in achieving lean body mass, desired body weight, and improved strength (as reflected in bench press testing). However, the predominant oral supplement form used in research and commercially is creatine monohydrate, which is converted to phosphocreatine intracellularly.

2. Historical Discovery and Scientific Context

2.1 Discovery of Phosphocreatine

The biological investigation of creatine originated in 1832 with its isolation from skeletal muscle as a nitrogenous organic compound, named "creatine" (from Greek kreas, meaning flesh). Early studies, constrained by analytical limitations, focused solely on its tissue distribution until the discovery of phosphocreatine (PCr) in the early 20th century unveiled its metabolic role.

The discovery of phosphocreatine was reported by Grace and Philip Eggleton of the University of Cambridge and separately by Cyrus Fiske and Yellapragada Subbarow of the Harvard Medical School in 1927. Phosphocreatine was first isolated in 1927 from extracts of rabbit skeletal muscle by Cyrus H. Fiske and Yellapragada SubbaRow at Harvard University, who identified it as a compound consisting of creatine bound to phosphoric acid, initially termed "creatine-phosphoric acid." Independently in the same year, Philip Eggleton and Grace P. Eggleton at the University of Edinburgh reported the discovery of a similar labile phosphorus-containing substance in muscle, which they named "phosphagen" to denote its role as a readily available phosphate reserve.

These findings resolved earlier observations of an enigmatic "extra" inorganic phosphate in muscle extracts that increased during contraction and decreased during recovery, previously attributed to methodological artifacts.

Phosphocreatine was first isolated from frog muscles (Eggleton, Biochem. J. 21, 190, 1927) and cat muscles (Fiske et al., J. Biol. Chem. 81, 629, 1929). A pivotal breakthrough occurred in 1933 with the characterization of creatine kinase (CK), which mediates the reversible phosphorylation between creatine and ATP (Cr + ATP ↔ PCr + ADP), establishing the enzymatic foundation of the energy buffer theory.

2.2 Early Scientific and Clinical Interest

In 1926, Chanutin surmised, based on what was probably one of the first creatine supplementation trials in the history of mankind, that creatine is absorbed by the intestine and thus can be taken up rather quantitatively from alimentary sources such as fresh fish and meat. Radioisotope tracer studies in the 1950s revealed dynamic PCr homeostasis in skeletal muscle.

The classical "CK-PCr" model emerged with three points: PCr as a mobile phosphate carrier overcoming ATP diffusion constraints; compartmentalized CK isoforms enabling directional energy transfer; and ATP/PCr buffering maintaining cellular energy homeostasis. This framework not only shaped exercise bioenergetics but also revolutionized understanding of energy dysregulation in myocardial ischemia and neurodegenerative diseases.

Therapeutic use of exogenous phosphocreatine in cardiac and muscle disease gained momentum through the latter decades of the twentieth century, particularly in Soviet and European research centers, and led to pharmaceutical preparations. Phosphocreatine is formed in muscular tissue by phosphorylation of creatine, and it has a fundamental role in maintaining valid muscle contraction.

3. Key Constituents, Biochemistry, and Mechanisms of Action

3.1 The Creatine Kinase / Phosphocreatine System

The pleiotropic effects of creatine (Cr) are based mostly on the functions of the enzyme creatine kinase (CK) and its high-energy product phosphocreatine (PCr). Multidisciplinary studies have established molecular, cellular, organ, and somatic functions of the CK/PCr system, in particular for cells and tissues with high and intermittent energy fluctuations. These studies include tissue-specific expression and subcellular localization of CK isoforms, high-resolution molecular structures and structure–function relationships, transgenic CK abrogation, and reverse genetic approaches. Three energy-related physiological principles emerge: the CK/PCr system functions as (a) an immediately available temporal energy buffer, (b) a spatial energy buffer or intracellular energy transport system (the CK/PCr energy shuttle or circuit), and (c) a metabolic regulator.

The CK-catalyzed reaction is fully reversible, and its final output will depend on the local concentrations of substrates and products. In vertebrates, four evolutionarily related CK genes are responsible for the production of five different but homologous CK isoforms: two mitochondrial MtCK isoforms forming octamers, represented by ubiquitous u-MtCK (CKMT1) and sarcomeric s-MtCK (CKMT2), and three cytosolic CK dimers, represented by muscle-type MM-CK dimers, brain-type BB-CK dimers, and a cardiac-specific MB-CK hybrid isoform.

The PCr energy shuttle concept is based on the specific subcellular localization of CK isoenzymes at these various sites and on the high cytosolic concentrations of free creatine (5–10 mM) and phosphocreatine (20–45 mM) compared to ADP (0.02–0.04 mM) and ATP (3–5 mM).

3.2 ATP Buffering and Rapid Energy Transfer

Within the skeletal muscle cell at the onset of muscular contraction, phosphocreatine (PCr) represents the most immediate reserve for the rephosphorylation of adenosine triphosphate (ATP). As a result, its concentration can be reduced to less than 30% of resting levels during intense exercise.

Phosphocreatine can anaerobically donate a phosphate group to ADP to form ATP during the first two to seven seconds following an intense muscular or neuronal effort. Conversely, excess ATP can be used during a period of low effort to convert creatine to phosphocreatine.

The function of creatine kinase (CK) has two aspects: (1) phosphocreatine (PCr) via the CK reaction buffers the cellular ATP and ADP concentrations; and (2) transport of high-energy phosphates is predominantly in the chemical form of PCr. This predominance of PCr is a consequence of the maintained ATP, ADP, and total creatine levels and of the apparent equilibrium constant of the reaction.

The creatine kinase system has a dual role in intracellular energy metabolism — functioning as an energy buffer to restore depleted ATP levels at sites of high ATP hydrolysis, and transferring energy in the form of phosphocreatine from the mitochondria to other parts of the cell by a process involving intermediate energy carriers, several enzymatic reactions, and diffusion through various intracellular structures.

3.3 PCr Resynthesis and Mitochondrial Respiration

The resynthesis process of PCr simply involves the rephosphorylation of creatine by aerobically produced ATP (with the release of protons); it has both a fast and slow component, each proceeding at a rate that is controlled by different components of the creatine kinase equilibrium.

The mechanism of metabolic regulation of mitochondrial respiration in cardiac muscle cells was studied experimentally in permeabilized heart fibres. The experiments showed that the rate of mitochondrial respiration could be controlled by local production of ADP by mitochondrial creatine kinase in the intermembrane space of mitochondria.

3.4 Non-Energy (Pleiotropic) Mechanisms

Beyond its role as an energy buffer, phosphocreatine engages multiple cellular signaling pathways. Phosphocreatine (PCr), a naturally occurring creatine phosphorylated molecule, is a high-energy phosphate compound that also has anti-apoptosis and anti-oxidative stress effects. It is precisely because of its role in maintaining energy homeostasis that PCr is widely used in diseases related to energy damage. In the regulation of cell signaling, PCr mainly plays a role through MAPK, NF-κB, PI3K/AKT, ERK/Nrf2/HO-1, and JAK2/STAT3.

The reversible conversion of Cr and ATP into PCr and ADP by creatine kinase, generating highly diffusible PCr energy reserves, is certainly an important element. However, some protective effects of Cr and analogues cannot be satisfactorily explained solely by effects on the cellular energy state.

Evidence from liposome model systems supports the interaction of PCr with different zwitterionic phospholipids. PCr can directly bind to phospholipid-containing membranes with low affinity, alters structural and conformational parameters of phospholipid liposomes, and protects phospholipid liposomes and erythrocytes from permeabilization induced by melittin, doxorubicin, hypoosmotic stress, or saponin. These results suggest that the interaction between PCr and membrane phospholipids may not only protect cellular membranes against various insults but could also have implications for many physiological membrane-related functions that are relevant for health and disease.

The possible mechanisms of action of applying exogenous PCr include supplying energy to myocardial cells, increasing myocardial contractility, stabilizing cell membrane structure, and reducing cell peroxidation damage.

4. Scientific Evidence by Area of Use

4.1 Cardiac Protection and Cardiovascular Disease

Phosphocreatine (PCr) plays an important role in the energy metabolism of the heart and a decrease in its intracellular concentration results in alteration of myocardium energetics and work. Phosphocreatine is a key component in the intracellular system of energy buffering and transports from the site of energy production to the site of energy utilization to ensure that supply meets the high and dynamic demands of the heart.

Meta-analysis evidence: A meta-analysis was conducted of all randomized and matched trials that compared PCr with placebo or standard treatment in patients with coronary artery disease or chronic heart failure or in those undergoing cardiac surgery. Investigators systematically searched PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials, and Google Scholar up to 1 November 2015. The primary outcome was all-cause mortality; secondary outcomes included inotrope use, ejection fraction (EF), peak creatinine kinase-myocardial band (CK-MB) release, and the incidence of major arrhythmias, as well as spontaneous recovery of heart performance in the subgroup of patients undergoing cardiac surgery with cardiopulmonary bypass.

The investigators identified 41 controlled trials, of which 32 were randomized. Patients receiving PCr had lower all-cause mortality when compared with the control group [61/1731 (3.5%) vs 177/1667 (10.6%); OR: 0.71, 95% CI: 0.51–0.99; P = 0.04; I² = 0%; with 3,400 patients and 22 trials included]. Phosphocreatine administration was associated with higher LVEF (MD: 3.82, 95% CI: 1.18–6.46; P = 0.005; I² = 98%), lower peak CK-MB release (MD: −6.08, 95% CI: −8.01, −4.15; P < 0.001; I² = 97%), lower rate of major arrhythmias (OR: 0.42; 95% CI: 0.27–0.66; P < 0.001; I² = 0%), lower incidence of inotropic support (OR: 0.39, 95% CI: 0.25–0.61; P < 0.001; I² = 56%), and a higher level of spontaneous recovery of heart performance after cardiopulmonary bypass (OR: 3.49, 95% CI: 2.28–5.35; P < 0.001; I² = 49%).

It is important to note methodological limitations identified in the literature. A major limitation of these meta-analyses was the inclusion of studies with high risk of bias and heterogeneous patient populations. The high I² values (up to 98%) for some outcomes indicate substantial heterogeneity across studies, limiting the confidence of pooled estimates.

Cardiac surgery — randomized controlled trial: This study tested the hypothesis that phosphocreatine (PCr), administered intravenously and as cardioplegia adjuvant in patients undergoing cardiac surgery with prolonged aortic cross-clamping and cardiopulmonary bypass (CPB) time, would decrease troponin I concentration after surgery. The randomized, double-blind, placebo-controlled pilot study included 120 patients undergoing double/triple valve repair/replacement under cardiopulmonary bypass. In this trial, phosphocreatine had no beneficial effect on clinical outcomes after surgery. This negative result, published in 2023, stands in tension with the earlier meta-analyses and highlights continued uncertainty in the field.

Earlier surgical evidence: In valve replacement operations on 78 patients with acquired heart disease, the efficiency of phosphocreatine in intraoperative protection of ischemic myocardium was evaluated by clinical, morphologic, and biochemical methods. Phosphocreatine (8 to 10 mmol/L) in a blood cardioplegic solution was used in operations on 41 patients; in the control group (37 patients) standard blood cardioplegia was used. In the group with phosphocreatine treatment, investigators observed more rapid recovery of hemodynamics after release of the aortic cross-clamp, a decreased frequency of fibrillation, and more frequent restoration of sinus rhythm even if there were sinus rhythm disturbances before aortic cross-clamping. Analysis of biopsy samples taken from the right ventricle showed protection of the sarcolemma against ischemic damage afforded by phosphocreatine and complete preservation of high-energy phosphates. These results confirm that phosphocreatine is an effective additional cardioprotective agent when used in cardioplegic solutions.

Evidence strength (cardiac): The body of clinical evidence for cardiac applications of PCr is substantive in volume (41 controlled trials identified in one meta-analysis), and the pooled mortality signal is statistically significant. However, the heterogeneity of included studies, risk-of-bias concerns, and the 2023 null result from a well-designed RCT mean the evidence must be characterized as promising but not conclusive. PCr is used as a pharmaceutical agent in several countries for cardiac indications, but has not received regulatory approval for this indication in the United States or the EU as a standalone medicine.

4.2 Skeletal Muscle Performance and Exercise

Within the skeletal muscle cell at the onset of muscular contraction, phosphocreatine (PCr) represents the most immediate reserve for the rephosphorylation of ATP. Its concentration can be reduced to less than 30% of resting levels during intense exercise. A fall in the level of PCr appears to adversely affect muscle contraction and therefore power output in a subsequent bout; maximising the rate of PCr resynthesis during a brief recovery period will be of benefit to an athlete involved in activities which demand intermittent exercise.

By increasing intracellular creatine content, oral creatine ingestion conceivably stimulates operation of the creatine kinase (CK)/phosphocreatine (PCr) system, which in turn facilitates muscle relaxation. The effect of oral creatine supplementation on high-intensity exercise performance has been extensively studied and its ergogenic potential in young healthy subjects is now well documented.

Studies have consistently shown that creatine supplementation increases intramuscular creatine concentrations, which may help explain the observed improvements in high intensity exercise performance leading to greater training adaptations.

In a normal diet that contains 1–2 g/day of creatine, muscle creatine stores are about 60–80% saturated. Evidence is accumulating to suggest that creatine supplementation can beneficially impact on muscle protein and glycogen synthesis.

Evidence strength (exercise performance): The evidence that increasing intramuscular PCr stores via creatine supplementation improves high-intensity, short-duration exercise performance is among the strongest in sports nutrition research, supported by numerous controlled trials and endorsed by the International Society of Sports Nutrition. It is important to note that oral creatine supplementation augments endogenous PCr stores; direct oral administration of exogenous PCr is not the conventional supplementation approach, and the mechanism of benefit is indirect (through upregulation of the CK/PCr system).

4.3 Neuroprotection and Brain Ischemia

Phosphocreatine (PCr) is a natural compound which can donate high-energy phosphate group to ADP to synthesize ATP, even in the absence of oxygen and glucose. At present, it is widely used in cardiac and renal ischemia-reperfusion (IR) disease.

Dietary creatine supplementation as a mono-agent pre-injury treatment has been shown to afford significant neuroprotection in animal models of TBI as well as other conditions such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and cerebral ischemia. Increased phosphocreatine availability and ATP synthesis, in conjunction with reduced mitochondrial impairment and improved calcium dynamics, are thought to contribute to the neuroprotective actions of creatine observed in these models.

Rats pretreated with PCr and exposed to focal cerebral ischemia injury had better neurologic scores, less infarction volume, fewer ultrastructural histopathologic changes, lower thiobarbituric acid reactive substances (TBARS) levels, and reduced apoptosis as compared with the control group.

Numerous clinical studies suggested favorable effects of phosphocreatine (PCr) supplementation in different patient populations including congestive heart failure, cardiac surgery, myocardial infarction, and cerebral ischemia.

Creatine has been safely administered to patients affected by several neurological diseases, yet it has never been tested in human brain ischemia, the condition where its rationale is strongest.

Evidence strength (neuroprotection): The neuroprotective evidence for PCr remains largely preclinical (animal studies and in vitro models). Well-controlled human clinical trials for PCr in brain ischemia or acute stroke are lacking as of available evidence. The mechanistic rationale is compelling and consistent across multiple model systems, but translation to clinical benefit in humans has not been established by adequately powered RCTs in neurological indications.

4.4 Parkinson's Disease and Neurodegenerative Conditions

The creatine kinase / PCr energetic system is endowed with antioxidant and neuroprotective properties and plays a pivotal role in brain energy homeostasis. Studies have investigated the neuroprotective effect of creatine and PCr against 6-hydroxydopamine (6-OHDA)-induced mitochondrial dysfunction and cell death in rat striatal slices, used as an in vitro Parkinson's model, including the possible involvement of the PI3K/Akt/GSK3β signaling pathway.

Creatine has emerged as a safe nutritional supplement not only to increase muscle mass and performance, prevent disease-induced muscle atrophy, and improve rehabilitation, but also to strengthen cellular energetics in general. This represents the physiological basis for the beneficial effects of creatine supplementation in the treatment of multiple pathologies that display bioenergetic dysregulation, such as myopathies or neurodegenerative diseases.

Evidence strength (neurodegeneration): Evidence here comes principally from preclinical models and small pilot trials. Phase III trials of oral creatine (which acts via PCr) in Parkinson's disease have produced null results, indicating that the in vitro and animal findings have not translated to clinical efficacy in this context.

4.5 Diabetic Cardiomyopathy and Metabolic Disease

Phosphocreatine (PCr) plays a major metabolic role in cardiac muscular cells, including intracellular concentration of ATP, which affects the activity of the myocardium. PCr might improve oxidative phosphorylation and electron transport capacity in mitochondria impaired by hyperglycemia in vivo and in vitro, suggesting a protective effect against diabetic cardiomyopathy (DCM) through the JAK2/STAT3 signaling pathway.

Further research on PCr has found that PCr also has a positive role in the treatment of other diseases, including diabetes-induced liver injury, kidney injury, cerebral ischemia-reperfusion injury, and neurodegenerative diseases. This body of evidence is predominantly derived from preclinical (animal and cell culture) studies. Well-powered human RCTs in these metabolic disease areas are not well represented in the literature to date.

4.6 Membrane Stabilization

A broad spectrum of beneficial effects has been ascribed to creatine (Cr), phosphocreatine (PCr), and their cyclic analogues. Research published in PMC demonstrates that PCr interacts directly with membrane phospholipids. With intracellular concentrations up to 30–40 mM and its rapid diffusibility, PCr together with CK isoforms provides an efficient energy buffer and transport system that maintains cellular energy homeostasis by restoring global and local ATP pools. These direct membrane interactions represent a mechanism of cytoprotection that is distinct from the CK/ATP energy buffering function, though this area of evidence remains at the basic science level.

5. Body Systems and Health Areas

Cardiovascular system: PCr is commonly used as a cardioprotective drug for conditions such as ischemic heart disease, myocardial fibrosis, myocardial infarction, arrhythmia, and myocarditis.
Skeletal muscle / musculoskeletal system: Phosphocreatine plays a particularly important role in tissues that have high, fluctuating energy demands such as muscle and brain. The immediate energy buffering role in skeletal muscle is fundamental to all high-intensity physical activity.
Central nervous system / brain: Phosphocreatine serves as a rapidly mobilizable reserve of high-energy phosphates in skeletal muscle and the brain of vertebrates.
Reproductive system: In the testes, sperm are exposed to the highest known creatine concentration in any mammalian tissue studied. Extracellular phosphocreatine, ATP, and creatine are proposed to be involved in sperm metabolism.
Renal system: Phosphocreatine and creatine cyclize to creatinine, which is excreted by renal glomeruli; the clearance rate is an important clinical diagnostic tool.
Mitochondrial / energy metabolism: The CK/PCr circuit is central to mitochondrial respiratory regulation across all high-energy tissues.

6. Dosage Forms and Reported Clinical Dosages

Phosphocreatine is not meaningfully bioavailable as an intact molecule when administered orally, as it is rapidly degraded in the gastrointestinal environment and blood. Consequently, clinical use of exogenous PCr occurs by parenteral (intravenous or intraoperative) routes; enhancement of endogenous PCr stores is achieved via oral creatine supplementation.

6.1 Intravenous / Intraoperative Use (as reported in studies)

In a randomized, double-blind, placebo-controlled pilot study of 120 patients undergoing double/triple valve repair/replacement under cardiopulmonary bypass, the treatment group received: intravenous administration of 2 g of PCr after anesthesia induction; 2.5 g of PCr in every 1 L of cardioplegic solution (concentration = 10 mmol/L); intravenous administration of 2 g of PCr immediately after heart recovery following aorta declamping; 4 g of PCr at intensive care unit admission.

Phosphocreatine at 8 to 10 mmol/L in a blood cardioplegic solution was used in operations on 41 patients with acquired heart disease.

The dosages at which phosphocreatine displays pharmacological properties in animals generally range between about 0.5 mg/kg and about 6 mg/kg. In therapy, they are administered to patients suffering from pathologic conditions by intramuscular or intravenous route in a daily dosage ranging between about 200 and about 400 mg. Pharmaceutical preparations contain the active ingredient in an amount of about 200 mg.

6.2 Preclinical (Animal) Dosing (as reported in studies)

In a rat model of focal cerebral ischemia-reperfusion, 400 mg/kg of disodium creatine phosphate was administered intravenously 30 min before operation.

6.3 Oral Creatine Supplementation Raising Endogenous PCr

While direct oral PCr supplementation is not standard, in a normal diet that contains 1–2 g/day of creatine, muscle creatine stores are about 60–80% saturated. Studies on oral creatine monohydrate loading have documented increased intramuscular PCr stores; loading protocols and maintenance dosages described in the ISSN position stand represent the established approach to elevating endogenous PCr. Direct oral "phosphocreatine" supplements exist commercially but their efficacy relative to creatine monohydrate has not been established in large clinical trials.

7. Safety Considerations and Drug Interactions

7.1 General Safety of the PCr/Creatine System

Creatine has emerged as a safe nutritional supplement not only to increase muscle mass and performance, prevent disease-induced muscle atrophy, and improve rehabilitation, but also to strengthen cellular energetics in general.

Phosphocreatine and creatine cyclize to creatinine, which is excreted by renal glomeruli; the clearance rate is an important clinical diagnostic tool. Because creatinine is the catabolite of the entire creatine/PCr pool, elevated creatinine levels during high PCr/creatine intake may confound clinical renal function assessments without representing true nephrotoxicity.

7.2 Intravenous PCr Administration Safety

Numerous clinical studies have suggested favorable effects of phosphocreatine (PCr) supplementation in different patient populations including congestive heart failure, cardiac surgery, myocardial infarction, and cerebral ischemia. The cardiac surgery RCT published in 2023 found that phosphocreatine had no beneficial effect on clinical outcomes after surgery, but also reported no significant safety signals attributable to PCr administration in its 120-patient population — though its size limits definitive safety characterization.

7.3 Creatinine Elevation and Renal Assessment

A known and well-characterized consequence of exogenous PCr or creatine administration is an increase in serum creatinine, the metabolic end-product excreted by glomerular filtration. This elevation reflects increased substrate availability rather than renal damage, but it is a recognized potential confounder of renal function monitoring in patients receiving PCr therapeutically. Clinicians interpreting creatinine values in patients receiving intravenous PCr should account for this effect.

7.4 Instability of the Molecule

The initial isolation of phosphocreatine proved challenging due to the compound's inherent instability; in acidic conditions, such as those used in trichloroacetic acid extractions, phosphocreatine rapidly hydrolyzed to free creatine. This chemical lability is relevant to formulation, storage, and preparation of intravenous PCr solutions, and explains why pharmaceutical preparations typically use stabilized salt forms such as the disodium tetrahydrate.

7.5 Non-Energy Mechanisms and Broader Safety Implications

In the regulation of cell signaling, PCr mainly plays a role through MAPK, NF-κB, PI3K/AKT, ERK/Nrf2/HO-1, and JAK2/STAT3. The engagement of these broad signaling pathways by exogenous PCr — particularly in clinical populations with pre-existing cardiovascular disease — is a mechanistic area warranting further characterization. The documented anti-apoptotic effects via these pathways have been the subject of investigation but their clinical implications in terms of safety remain incompletely defined.

7.6 Use in Specific Populations

No adequately powered clinical trials evaluating PCr safety specifically in pregnant women, pediatric populations, or patients with advanced renal failure have been identified in the sources reviewed. The intravenous clinical trials primarily enrolled adults undergoing cardiac surgery or presenting with cardiac disease, limiting generalizability of safety conclusions to other groups. The loss of cellular ATP due to oxygen and glucose deprivation during ischemia is a cause of tissue death — the therapeutic rationale that motivates PCr use in acute settings — but this also underscores that PCr administration in the context of severe ischemia should be treated as a clinical pharmacological intervention, not a general-use supplement.

References

Health Conditions

Health conditions that Phosphocreatine may help support.

No conditions available.

Body Systems

Body systems that Phosphocreatine may help support.

No body systems available.