It is still largely accepted, that the main rout of Cr biosynthesis in humans involves formation of guanidinoacetae in the kidney, its transport through the blood and its methylation to Cr in the liver, though all the precurces of guanidinoacetate are formed in other tissues, for instance, a complete urea cycle operates actively only in liver, the main site of Arginine (Arg) biosynthesis is, however, the, kidney, Citrulline is synthesized in the liver or small intestine then taken up by the kidney to be converted into Arg.
An important practical aspect of Cr biosynthesis to add is that methyl groups (Methyonine and Choline) on a normal equilibrated diet, also Folic acid and/or vit B12 and B6 deficiency may substantially impair the Cr biosynthesis.
Although the pathway of Cr metabolism in humans seem simple, the situation is complicated by the fact that most tissues lack several enzymes required, thus necessitating transport of intermediates between the tissues through the blood to allow the whole cascade of reactions to proceed. This, on the other hand, gives us the perfect opportunity to monitor these events by available hands on biochemical tools in laboratory and in the field tests. With the assumption of an average content in muscle of 30mM of total Cr and a quantitative uptake of the compound by the digestive tract, this loss could be compensated by ingestion of 500gof raw meat per day. Because Crn is a very poor substrate of the Cr transporter, because no other specific saturable uptake mechanism exists for Crn, and because Crn, most likely due to its nonionic nature, is membrane permeable, Crn constantly diffuses out of the tissues into the blood and is excreted by the kidneys into the urine. Because the rate of non-enzymatic formation of Crn from Cr is nearly constant, and because near to 90% of the total bodily Cr is to be found in muscle tissue, 24-h urinary Crn excretion is frequently used as a rough measure of total muscle mass. However, this approach sufferers various limitations. Twenty to twenty five percent of the in vivo conversion of CP into Crn may proceed via phosphoril-creatinine (CrnP) as an intermediate.