Five more references:

Dumler 1979: Effects of Orotate Administration on the Normal Rat Kidney
Gotz 1982: Electron microscopic and morphometric studies on the in vitro differentiation of mitochondria in neurons of hippocampus explant cultures as affected by orotic acid and sodium orotate
Krug 1977: Effects of orotic acid and pirazetam on cortical bioelectrical activity in rabbit
Lindner 1980: The effect of active substances on nerve fiber regeneration in nerve tissue cultures
Motyl 1991: Urinary excretion of purines in sheep with experimental orotic aciduri

I've included references to potassium and sodium orotate, these are relevant because, along with lithium, they are all group 1 alkali metals on the periodic table of elements. Of critical importance is the fact that they all have +1 oxidation states. This means ions from these metals all have a electron charges of +1, this is important because it determines the molecular structure of the orotate coordination complex. Zinc for instance, has a electron charge of +2, so it actually forms an ionic bond with two orotate molecules. As a result of this double orotate zinc bond, the zinc orotate complex is hypothesized to not be able to dock with the uridine monophosphate synthetase (UMPS) enzyme.


Peer review:
The EFSA Journal (2009) 1187, 1-25: Orotic acid salts as sources of orotic acid and various minerals added for nutritional purposes to food supplements.

The European Food Safety Authority was asked to provide a scientific opinion of the safety of orotic acid and several of its metal orotates. The panel conducted a diligent review on the safety of orotic acid. The panel establish a NOEL (No Observed Effect Level) at 50 mg orotic acid/kg bw/day. The panel further established a LOEL (Lowest Observed Effect Level) at 100 mg orotic acid/kg bw/day.

As expected, 500 mg orotic acid/kg was found to be carcinogenic. They additionally noted tumor-promoting effects down to 100 mg/kg (Sarma et. al., 1986). This carcinogenic effect is expected, orotic acid is essential for the synthesis of RNA and DNA, and it is reasonable to presume that a massive excess of orotic acid would influence cell growth. A parallel analogy would be akin to giving a plant so much fertilizer that it dies from hypotonicity. The panel referenced RTECS RM3180000 (Registry of Toxic Effects of Chemical Substances) for acute toxicity and LD50, which in mouse was 2 g/kg oral, 841 mg/kg intraperitoneal, and 770 mg/kg intravenous. The Hazardous Substances Data Bank has an extensive collection of data that was not referenced in this work, however their conclusions are consistent with available data and their opinion regarding safe upper limits should be considered authoritative.

With that said, a number of problems exist with the conclusions reached by this panel regarding the utility of metal orotates.

The panel asserts their opinion regarding bioavailability of all metal orotates on the basis of a single study conducted with zinc orotate (Andermann G and Dietz M, 1982). To put it bluntly, making this statement on the basis of one report that studied one element is absurd, however to the panels defense no documentation was supplied by the petitioners. Transitional metals, such as zinc, do not have the same properties as alkalis. Furthermore the zinc cation has a charge of +2 and orotate is -1, this means zinc forms an ionic bond with two orotate molecules; it may not be able to dock with the uridine monophosphate synthetase (UMPS) enzyme, assuming it doesn't dissolve into separate free elemental zinc and orotate molecules.


Assuming that orotic acid is not precipitated from the kidneys as a free acid, what basis is there to believe that oral, intraperitoneal, or intravenous intake of orotic acid remains in it's free acid state (Christensen, 1983)? Christensen suggested in this review that orotic acid most likely binds with sodium to form sodium orotate monohydrate. The ability of orotidine 5'-phosphate decarboxylase to bind with metal coordinations has not been fully established, let alone the ability of this enzyme to decarboxylate them. More research is needed, particularly with lithium orotate as it has a higher charge density than sodium. Nearly every study regarding lithium orotate has demonstrated findings that differ from lithium carbonate, however no effort has been put forward to explain these findings. The panels statement regarding bioavailability is conjecture.

Wenzel et. al., 1979, gave sodium orotate to rats and had this to say about the subject: "The total number of ribosomes increases following the application of orotic acid by 20%, of sodium-orotate by 48% and of methylglucamine-orotate by 23% compared to the controls (alpha = 0,1%). 4. Sodium-orotate shows with reference to the neuronal development the clearest stimulatory effect. After 20 days in vitro the total number of ribosomes is by 60% higher at the treated cultures than in the controls."

My Preliminary Research Notes:
Here are my preliminary notes on lithium orotate, I was planning to publish a paper, but do not have time to finish or publish it. These are my initial notes I typed up back in August 2013, I was planning to suggest the use of lithium orotate as a control to study the effects of elemental lithium in the drinking water, but it became apparent while writing these notes that lithium orotate did not have the same pharmacodynamics as the other forms of lithium. My posts in this forum thread, including the EFSA review, can be used freely by others, all I ask for is appropriate credit. Furthermore, any part may be incorporated into Wikipedia. I simply don't have time to dedicate towards furthering this subject.

lithium 1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarboxylate monohydrate:



Lithium orotate (lithium orotate monohydrate) is a metal complex comprised of orotate and water ligands non-covalently bonded to lithium, it is a salt of orotic acid and an organic compound, with a formula Li+ * C5H3N2O4- * H2O. It is synthesized exclusively as a monohydrate, for use as a dietary supplement.

While orotic acid can be supplied in anhydrous form, this form has no known applications.

Synthesis:

Orotic acid:
C5H4N2O4

Lithium orotate:
Li + C5H4N2O4 → LiC5H3N2O4 + H

Lithium orotate monohydrate:
LiC5H3N2O4(s) → Li+(aq) + C5H3N2O4-(aq)

For reference, lithium carbonate:
Li2CO3(s) + 2H+(aq) → 2Li+(aq) + H2O(l) + CO2(g)

Lithium is a highly reactive element from the alkali metal group that can only be ingested as a chemical compound, it is reacted as a cation (Li+) with orotic acid (C5H4N2O4-) to produce a salt compound that can be ingested. During synthesis, the carboxyl group in orotic acid is deprotonated and its conjugate base, orotate (C5H3N2O4-), forms a carboxylate anion (RCOO-) that bonds with the lithium cation. As a result of this RCOO-Li+ bond it is not actually an organometallic compound, however it is often categorized as one. Orotate is presumed to function as a biochemical ligand within the lithium complex.

Some have expressed that the RCOO-Li+ bond is quickly broken once it enters the body, one study concluded that orotic acid was precipitated from the kidneys as an alkali metal orotate, and almost never it is free acid state. Under normal conditions, they concluded it was most likely precipitated as sodium orotate. However, with lithium having a smaller atomic radius and greater charge density, this compound is unlikely to readily dissolve.

It is often categorized as an organometallic compound, although strictly speaking it is not due to its carboxylate anion bond (RCOO-Li+).

Orotate (orotic acid) was historically believed to be vitamin, however it was discovered that the body manufacturers this compound as a component of pyrimidine metabolism. Orotate is covalently linked with a phosphorylated ribosyl unit. The covalent linkage between the ribose and pyrimidine occurs at position C1[4] of the ribose unit, which contains a pyrophosphate, and N1 of the pyrimidine ring. Orotate phosphoribosyltransferase (a/k/a "PRPP transferase") catalyzes the net reaction yielding orotidine monophosphate (OMP): Orotate + 5-Phospho-α-D-ribose 1-diphosphate (a/k/a "PRPP") = Orotidine 5'-phosphate + Pyrophosphate

What happens to lithium when orotate binds with the ribosyl and is catalyzed into orotidine monophosphate has not been studied, however pyrimidine metabolism happens throughout the body. Historically it was assumed that lithium and orotate separated principally within the brain, however no human studies support this conclusion empirically. One study in rats measured brain plasma levels and found no statistical difference in lithium concentrations between equivalent doses of elemental lithium from lithium carbonate, lithium orotate, or lithium chloride. Another study in rats concluded that "the 24 h brain concentration of lithium after lithium orotate was approximately three times greater than that after lithium carbonate."

It is also worth noting that one study involving patients with kidney stones concluded that orotic acid is precipitated from the kidneys most likely as sodium orotate, due to it's chemical properties; lithium and sodium are both alkali metals, however lithium has greater electronegativity than sodium. If this is correct lithium may stay attached to the orotate molecule, or re-bond to orotic acid, due to its greater affinity. Whatever the case, the authors strongly asserted that orotic acid is not precipitated as a free acid and that orotate salts can be found in kidney stones. Furthermore the FDA literature for lithium carbonate states that “sodium loss may reduce the renal clearance of lithium and increase serum lithium levels with risk of lithium toxicity.”, if it is the case that orotate is precipitated as a sodium bonded salt this statement may explain Smith DF's findings from 1979. Additionally if Kling did not account for reduced kidney function this would explain why he noted higher lithium concentrations within the brain during his 1978 study.

Continuing with the metabolic process of orotate, uridine monophosphate (UMP) is formed from Orotidine 5'-monophosphate in a decarboxylation reaction catalyzed by the enzyme orotidylate decarboxylase. Uncatalyzed, the decarboxylation reaction is extremely slow (estimated to occur on average one time per 78 million years). Adequately catalyzed, the reaction takes place in one second.[2] In humans, the orotidylate decarboxylase function is carried out by the protein UMP synthase.[3] Defective UMP synthase can result in orotic aciduria, a metabolic disorder.

As previously stated, lithium is, at least initially, non-covalently bonded to orotate via this carboxyl group. It is not known if it is still attached prior to decarboxylation, separates during decarboxylation, interacts with decarboxylation, or inhibits decarboxylation. Hypothetically if UMP synthase was inhibited by lithium orotate it should produce the same symptoms of orotic aciduria, no cases of this have been reported. Another hypothetical is that if the carboxyl group stayed attached to the metal complex you could be left with CO2- * Li+ * H2O, which maybe would convert itself into HCO3 + H2, which is lithium bicarbonate and dihydrogen respectively. All of this is speculation, lithium orotate may not even make it through the gastric track intact.

The ratio of elemental lithium to lithium orotate is 25.94, this number is derived by dividing the molar mass of lithium orotate monohydrate by the molar mass of elemental lithium. Likewise, 5.32 is the ratio of elemental lithium to lithium carbonate, 7.04 for lithium citrate, 7.92 for lithium sulfate, and 20.03 for lithium aspartate.

While it is well established that lithium can induce nephropathy in high doses, one study conducted with rats documented additional kidney function impairment with lithium orotate relative to an equivalent dose of elemental lithium from lithium carbonate (“2 mmol lithium kg-1”), which if derived correctly implies a lithium orotate dosage of 934 mg/kg. The LD50 of orotic acid in mouse is 2000 mg/kg[ref:Aldrich], indicating a possible error in the study. Another study in cats documented nephropathy after administration of orotic acid, and in this instance the average dose of orotic acid was 450 mg/kg. At first glance this appears damning, however orotic acid is an essential molecule produced by the body and these studies were conducted with extremely high dosages; using an average adult weight of 62 kg, dosing at 450 mg/kg would equate to 27900 mg of orotic acid. The point at which the combined effects of orotate and lithium impair kidney function is unknown, however dietary supplement labeling typically recommends a dosage of just 240 mg per day (9.25 mg elemental lithium, 24.02 mg water, 206.73 mg orotate) and no case report or study has indicated adverse events at a dose this low. Individuals with renal impairment should consult a physician before taking this, or any other, supplement.

Lithium orotate administered at a rate equivalent to lithium carbonate, derived from molecular weights, is 4.873 times that of lithium carbonate. For instance, lithium orotate administered at 4386 mg is equivalent to 900 mg of lithium carbonate in terms of elemental lithium. It is not known if this high a dosage is safe and this is one of the reasons why it is not used in the treatment of psychiatric disorders. Emerging research however is indicating that even trace amounts of lithium can have positive effects; at the labeled dose of 240 mg, lithium orotate is capable of delivering roughly 24 times the amount of elemental lithium that was measured in one study. Furthermore if lithium is somehow incorporated into DNA, RNA, or protein synthesis by way of the orotate bond it could in fact be more bioavilable than any other form of lithium. Little is known about the pharmacokinetics of lithium orotate, as the psychiatric community abandoned it when the FDA approved lithium carbonate and lithium citrate for the treatment of mania, circa 1970s.

Ideas, Tests, Hypos, Applications:

• Lithium salt serum test strips (orotate salts are precipitated through kidneys).
• 14C radiocarbon of orotate salts to study for incorporation into proteins.
• Lithium orotate as a medicine to correct conditions causing alkaline urine.
• Lithium orotate adjunct to lithium carbonate (compounding to two).
• Acute injections of lithium orotate for the rapid control of mania in emergency care settings.
• Orotate coordinations for the delivery of drugs in vitro via ODCase decarboxylation and pyrimidine salvage pathway recycling.