Non-enzymatic cyclization of creatine ethyl ester to creatinine

Giese, Matthew W.; Lecher, C S

doi:10.1016/j.bbrc.2009.07.151

Cited by 22 publications

(17 citation statements)

References 13 publications

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“…However so far, only the Cr derivative Cr ethyl ester has been used to treat SLC6A8-deficient patients (Fons et al 2010), but this compound failed to replenish their brain Cr concentration, as well as to improve their neurological status. This is probably due to the non-enzymatic conversion of Cr ethyl ester directly to creatinine, before it reaches CNS (Giese and Lecher 2009). For the treatment of SLC6A8-deficient patients, no data are available so far for the use of other Cr derivatives, in particular those that seem to cross BBB (PCr-Mg-complex acetate and creatinyl amino acids).…”

Section: Creatine Derivatives For a Better Crossing Of Bbb?mentioning

confidence: 95%

Creatine and guanidinoacetate transport at blood‐brain and blood‐cerebrospinal fluid barriers

Braissant

2012

J of Inher Metab Disea

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While it was thought that most of cerebral creatine is of peripheral origin, AGAT and GAMT are well expressed in CNS where brain cells synthesize creatine. While the creatine transporter SLC6A8 is expressed by microcapillary endothelial cells (MCEC) at blood-brain barrier (BBB), it is absent from their surrounding astrocytes. This raised the concept that BBB has a limited permeability for peripheral creatine, and that the brain supplies a part of its creatine by endogenous synthesis. This review brings together the latest data on creatine and guanidinoacetate transport through BBB and blood-CSF barrier (BCSFB) with the clinical evidence of AGAT-, GAMT- and SLC6A8-deficient patients, in order to delineate a clearer view on the roles of BBB and BCSFB in the transport of creatine and guanidinoacetate between periphery and CNS, and on brain synthesis and transport of creatine. It shows that in physiological conditions, creatine is taken up by CNS from periphery through SLC6A8 at BBB, but in limited amounts, and that CNS also needs its own creatine synthesis. No uptake of guanidinoacetate from periphery occurs at BBB except under GAMT deficiency, but a net exit of guanidinoacetate seems to occur from CSF to blood at BCSFB, predominantly through the taurine transporter TauT.

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Section: Creatine Derivatives For a Better Crossing Of Bbb?mentioning

confidence: 95%

Creatine and guanidinoacetate transport at blood‐brain and blood‐cerebrospinal fluid barriers

Braissant

2012

J of Inher Metab Disea

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“…Degradation of CEE can form either CRT through intramolecular ester hydrolysis, or CRN through 5-exotrig cyclization Adriano et al, 2011; Giese & Lecher, 2009a; Johnson, 1993) (Figure 1). The latter intramolecular reaction likely accounts for the undesired formation of CRN hydrochloride observed in the equilibrium esterification process used for the synthesis of CEE from CRT monohydrate (Mold, Gore, Lynch, & Schantz, 1955; Vennerstrom, 2005).…”

Section: Introductionmentioning

confidence: 99%

pH-Dependent Stability of Creatine Ethyl Ester: Relevance to Oral Absorption

Gufford

Ezell

Robinson

et al. 2013

Journal of Dietary Supplements

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Creatine ethyl ester hydrochloride (CEE) was synthesized as a prodrug of creatine (CRT) to improve aqueous solubility, gastrointestinal permeability, and ultimately the pharmacodynamics of CRT. We used high-performance liquid chromatography (HPLC) and proton nuclear magnetic resonance (NMR) to characterize the pH-dependent stability of CEE in aqueous solution and compared the permeability of CEE to CRT and creatinine (CRN) across Caco-2 human epithelial cell monolayers and transdermal permeability across porcine skin. CEE was most stable in a strongly acidic condition (half-life = 570 hours at pH 1.0) where it undergoes ester hydrolysis to CRT and ethanol. At pH ≥ 1.0, CEE cyclizes to CRN with the logarithm of the first order rate constant increasing linearly with pH. Above pH 8.0 (half-life = 23 sec) the rate of degradation was too rapid to be determined. The rate of degradation of CEE in cell culture media and simulated intestinal fluid (SIF) was a function of pH and correlated well with the stability in aqueous buffered solutions. The permeability of CEE across Caco-2 monolayers and porcine skin was significantly greater than that of CRT or CRN. The stability of CEE in acidic media together with its improved permeability suggests that CEE has potential for improved oral absorption compared to CRT.

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“…However, it was recently reported that CEE can be cyclized into creat inine through a non enzymatic reaction at physiolog ical conditions encountered during its transit into the gastrointestinal tract. Since this causes a rise in the creatinine blood level [30,31], this implies that ele vated serum creatinine does not always indicate impaired renal function, but may depend on the use of CEE supplements [30]. Data reported herein suggests that CEE may increase cognitive capacity, not only because it is a Cr source, but also because it may become a substrate of CK which transforms it into PCEE, a new phosphagen molecule.…”

Section: Discussionmentioning

confidence: 79%

Creatine ethyl ester: A new substrate for creatine kinase

et al. 2012

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The creatine kinase/phosphocreatine system plays a key role in cell energy buffering and trans\ud port, particularly in cells with high or fluctuating energy requirements, like neurons, i.e. it participates in the\ud energetic metabolism of the brain. Creatine depletion causes several nervous system diseases, alleviated by\ud phosphagen supplementation. Often, the supplementation contains both creatine and creatine ethyl ester,\ud known to improve the effect of creatine through an unknown mechanism. In this work we showed that puri\ud fied creatine kinase is able to phosphorilate the creatine ethyl ester. The Km and Vmax values, as well as tem\ud perature and pH optima were determined. Conversion of the creatine ethyl ester into its phosphorylated\ud derivative, sheds light on the role of the creatine ethyl ester as an energy source in supplementation for\ud selected individuals

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Non-enzymatic cyclization of creatine ethyl ester to creatinine

Cited by 22 publications

References 13 publications

Creatine and guanidinoacetate transport at blood‐brain and blood‐cerebrospinal fluid barriers

Creatine and guanidinoacetate transport at blood‐brain and blood‐cerebrospinal fluid barriers

pH-Dependent Stability of Creatine Ethyl Ester: Relevance to Oral Absorption

Creatine ethyl ester: A new substrate for creatine kinase

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