In regard to bioenergetics, phosphorylated cyclocreatine appears to have less affinity for the creatine kinase enzyme than phosphorylated creatine in terms of donating the high energy phosphate group (about 160-fold less affinity) despite the process of receiving phosphorylation being similar.[104][105] When fed to chickens, phosphorylated cyclocreatine can accumulate up to 60mM in skeletal muscle,[106] which suggests a sequestering of phosphate groups before equilibrium is reached.[105] Cyclocreatine still has the capacity to donate phosphate, however, as beta-adrenergic stimulated skeletal muscle (which depletes ATP and glycogen) exhibits an attenuation of glycogen depletion (indicative of preservation of ATP) with phosphocreatine.[102]
Creatine synthesis primarily occurs in the liver and kidneys.[2][16] On average, it is produced endogenously at an estimated rate of about 8.3 mmol or 1 gram per day in young adults.[16][17] Creatine is also obtained through the diet at a rate of about 1 gram per day from an omnivorous diet.[16][18] Most of the human body's total creatine and phosphocreatine stores are found in skeletal muscle, while the remainder is distributed in the blood, brain, and other tissues.[17][18]
There is a genetic condition known as gyrate atrophy of the choroid and retina, which is associated with a high level of Ornithine in the blood and a relative decrease in Arginine, which causes a relative creatine deficiency due to L-arginine being required to make creatine[478][479] and because high ornithine can suppress creatine synthesis (AGAT) in the glial cells of the retina.[475] This condition can be attenuated by either reducting ornithine in the diet[480] or by supplementing creatine, which is, in this instance, therapeutic.[481][482]

It is known that intracellular energy depletion (assessed by a depletion of ATP) stimulates AMPK activity in order to normalize the AMP:ATP ratio,[333][334] and when activated AMPK (active in states of low cellular energy[335] and colocalizes with creatine kinase in muscle tissue[336]) appears to inhibit creatine kinase via phosphorylation (preserving phosphocreatine stores but attenuating the rate that creatine buffers ATP). While phosphocreatine technically inhibits AMPK, this does not occur in the presence of creatine at a 2:1 ratio.[334] It seems that if the ratio of phosphocreatine:creatine increases (indicative of excess cellular energy status) that AMPK activity is then attenuated, since when a cell is in a high energy status, there is less AMP to directly activate AMPK.[334][336][337]