L-CARNITINE
DESCRIPTION
CARNITOR(r) (Levocarnitine) is (R)-3-carboxy-2-hydroxy-N,N,N-trimethyl-1-propanaminium hydroxide, inner salt. Levocarnitine is a carrier molecule in the transport of long chain fatty acids across the inner mitochondrial membrane. As a bulk drug substance it is a white powder with a melting point of 196-197Β°C and is readily soluble in water, hot alcohol, and insoluble in acetone. The pH of a solution (1 in 20) is between 6-8 and its pKa value is 3.8.
CLINICAL PHARMACOLOGY
CARNITOR(r) (Levocarnitine) is a naturally occurring substance required in mammalian energy metabolism. It has been shown to facilitate long-chain fatty acid entry into cellular mitochondria, therefore delivering substrate for oxidation and subsequent energy production. Fatty acids are utilized as an energy substrate in all tissues except the brain. In skeletal and cardiac muscle they serve as major fuel. Primary systemic carnitine deficiency is characterized by low plasma, RBC, and/or tissue levels. It has not been possible to determine which symptoms are due to carnitine deficiency and which are due to the underlying organic acidemia, as symptoms of both abnormalities may be expected to improve with carnitine. The literature reports that carnitine can promote the excretion of excess organic or fatty acids in patients with defects in fatty acid metabolism and/or specific organic acidopathies that bioaccumulate acyl CoA esters. 1 - 6
Secondary levocarnitine deficiency can be a consequence of inborn errors of metabolism. CARNITOR(r) may alleviate the metabolic abnormalities of patients with inborn errors that result in accumulation of toxic organic acids. Conditions for which this effect was demonstrated are: glutaric aciduria II, methyl malonic aciduria, propionic acidemia, and medium chain fatty acyl CoA dehydrogenase deficiency. 7,8 Autointoxication occurs in these patients due to the accumulations of acyl CoA compounds that disrupt intermediary metabolism. The subsequent hydrolysis of the acyl CoA compound to its free acid results in acidosis that can be life threatening. Levocarnitine clears the acyl CoA compound by formation of acyl carnitine which is quickly excreted.
Levocarnitine deficiency is defined biochemically as abnormally low plasma levels of free carnitine (less than 20 Β΅ mol/L at one week post term) and may be associated with low tissue and/or urine levels. Further, this condition may be associated with a ratio of plasma ester/free levocarnitine levels greater than 0.4 or abnormally elevated levels of esterified levocarnitine in the urine. In premature infants and newborns, secondary deficiency is defined as plasma free levocarnitine levels below age related normal levels.
BIOAVAILABILITY/PHARMACOKINETICS
In a relative bioavailability study in 15 healthy adult male volunteers CARNITOR(r) Tablets were found to be bio-equivalent to CARNITOR(r) Oral Solution. Following the administration of 1980 mg b.i.d., the maximum plasma concentration level (C max ) was 80 nmol/mL and the time to maximum concentration (T max ) occurred at 3.3 hours. There were no significant differences for AUC and urinary excretion observed between these two formulations.
In the same bioavailability study of 15 healthy adult males, CARNITOR(r) (Levocarnitine) Injection administered as a slow 3 minute bolus intravenous injection at a dose of 20 mg/kg showed that free levocarnitine plasma profiles are best fit by a two compartment model. Approximately 76% of free levocarnitine is eliminated in the urine. Using plasma levels uncorrected for endogenous levocarnitine, the mean distribution half life was 0.585 hours and the mean apparent terminal elimination half life was 17.4 hours following a single intravenous dose.
The absolute bioavailability of L-carnitine from CARNITOR(r) Tablets and Oral Solution was determined compared to the bioavailability of L-carnitine from CARNITOR(r) Injection Intravenous in 15 healthy male volunteers. After correction for circulating endogenous levels of L-carnitine in the plasma, absolute bioavailability was 15.1% Β± 5.3% for L-carnitine from CARNITOR(r) Tablets and 15.9% Β± 4.9% from the Oral Solution.
Total body clearance of L-carnitine (Dose/AUC including endogenous baseline levels) was a mean of 4.00 L/hr. Endogenous baseline levels were not subtracted since total body clearance of L-carnitine does not distinguish between exogenous sources of L-carnitine and endogenously synthesized L-carnitine. Volume of distribution of the intravenously administered dose above baseline endogenous levels was calculated to be a mean of 29.0 L Β± 7.1 L (approximately 0.39 L/kg) which is an underestimate of the true volume of distribution since plasma L-carnitine is known to equilibrate slowly with, for instance, muscle L-carnitine.
L-carnitine was not bound to plasma protein or albumin when tested at any concentration or with any species including the human. 9
METABOLISM AND EXCRETION
Five normal adult male volunteers, administered a dose of [ 3 H-methyl]-L-carnitine following 15 days of a high carnitine diet and additional carnitine supplement, excreted 58 - 65% of administered radioactive dose in 5 to 11 days in the urine and feces. Maximum concentration of [ 3 H-methyl]-L-carnitine in serum occurred from 2.0 to 4.5 hr after drug administration. Major metabolites found were trimethylamine N-oxide, primarily in urine (8% to 49% of the administered dose) and [ 3 H]-(gamma)-butyrobetaine, primarily in feces (0.44% to 45% of the administered dose). Urinary excretion of carnitine was 4% to 8% of the dose. Fecal excretion of total carnitine was less than 1% of total carnitine excretion. 10
After attainment of steady state following 4 days of oral administration of L-carnitine with CARNITOR(r) Tablets (1980 mg q12h) or Oral Solution (2000 mg q12h) to 15 healthy male volunteers, urinary excretion of L-carnitine was a mean of 2107 and 2339 Β΅ moles, respectively, equivalent to 8.6% and 9.4%, respectively, of the orally administered doses (uncorrected for endogenous urinary excretion). After a single intravenous dose (20 mg/kg) prior to multiple oral doses, urinary excretion of L-carnitine was 6974 Β΅ moles equivalent to 75.6% of the intravenously administered dose (uncorrected for endogenous urinary excretion).
Acetyl L-carnitine the bioJogically active form ofL-carnitine has been shown to
protect ceJJs throughout the body against age related degeneration. By facilitating
the transport of fatty acids into the cell's mitochondria, camitine enables dietary
fats to be converted to energy. One of the most common characteristics of ageing
is Joss of energy, ft is widely believed that one cause of this age related decline in
energy metabolism is due to Joss ofmitochondrial function. It has been hypothesized
that ageing could be due entirely to mitochondriaJ dysfunctiori. Mitochondria are
also referred to as the cellular powerhouses. They produce metabolic energy by a
process known as oxidative phosphorylation, which results in the production of
adenosine triphosphate (ATP), the key energy source in the body. Mitochondrial
membranes are considered by many scientists to be the lilcely subeellular site of
the age-related decline in mitochondrial function. It is believed that the decrease
in energy production with ageing is due to alteration of lipid composition and
content ofmitochondnal membranes. Cytochrome Co-oxidase an enzyme complex
in mitochondria, is a vital component of cellular energy processes and is responsible
for virtually all oxygen consumption in mammals.
The effects of ageing were dramatically demonstrated when scientists measured
cell energy activity and respiration rates in the heart mitochondria of rats. The
activity of the pyruvate earner as well as the rates of pyruvate - supported respiration
were both depressed (around 40%) in heart mitochondria in the older rates. When
acetyl L-carnitine was administered the rates of these metabolic functions were
completely restored to the JeveJ for young rats. This effect of acetyl-L-carnitine
was not due to changes in the content of pyruvate carrier molecules. The heart
mictochondrial content of cardiolipin, a Icey phospholipid necessary for
mitochondrial substrate transport, was markedly reduced (approx. 40%) in aged
rats. Supplementation with acetyl L-carnitine in them reversed the age associated
decline in cardiolipin content. As the changes in cardiolipin content were correlated
with changes in rates of pyruvate transport and oxidation, it was suggested that
acetyl L-carnitine reverses age related decrement in the mitochondrial pyruvate
metabolism by restoring the normal cardiolipin content.
Alterations in brain cell metabolism also occur with ageing. Acetyl L-carnitine
has been shown to counteract several mechanisms of brain cell damage. Acetyl
L-carnitine has been shown to protect the brain against temporary cerebral ischemia.
by mnintaining the cell's energy cycle. Some studies have shown that acetyl
L-caniitine protects the brain cells against glutamate and ammonia induced toxicity.
Circulation in the brain diminishes as people grow older, setting off a cascade of
pathological events that lead to neurological impairment.
Acetyl L-carnitine also appears to protect against some of the known negative
effects that ageing induces in the brain. In animal stroke models an 11 -point
neurologic deficit scoring system evaluated the treatment progression of acetyl
L-camitine against a control vehicle. Acetyl L-caroitine was shown to protect
brain cells against ischemic injury and to improve neurological outcome with the
treated animals showing significant improvement in comparison to controls. The
study suggested that acetyl L-carnifine may somewhere in near future be used in
hospital emergency wards to improve the prognosis of patients of strove who
otherwise have a little hope of full recovery.
In Aizheimer's disease, some studies have shown encouraging results while other
studies have shown no benefits. In one placebo controlled study it was seen that
patients under 62 years of age benefited more from acetyl L-carnitine than older
patients and as such, it was concluded that acetyl L-carnitine stows the progression
ofAIzheimer's disease in younger patients.
Acetyl L-carnitine enhances energy production in every cell of the body. Two
studies illustrate this unique ability ofALC to increase cellular respiration in ageing
models. In one study liver parenchyma} cells in old mice after feeding them a
1.5% solution of acetyl L-carnitiae for one month were studied. The results showed
a significant reversal in age-associated decline ofmitochondnal membrane function.
In another similar study the same conclusion about the ability of acetyl L-carnitine
in reversing the age-related mifochondrial decay was reached.
Acetyl L-carnitine may also facilitate nerve regeneration after injury. It is found
to have a significant neuroprotective effect against the degeneration oftraumatized
motor neurons. Treatment with acetyl L-carnitine in patients on anti-viral HIV
drugs may assist in the treatment of drug induced peripheral neuropathy.
in other studies conducted in diabetic rats it was found that supplementation with
acetyl L-carnitine can accelerate nerve regeneration after experimental injury and
can also potentially treat diabetic neuropathy.
INDICATIONS AND USAGE
CARNITOR(r) (Levocarnitine) is indicated in the treatment of primary systemic carnitine deficiency. In the reported cases, the clinical presentation consisted of recurrent episodes of Reye-like encephalopathy, hypoketotic hypoglycemia, and/or cardiomyopathy. Associated symptoms included hypotonia, muscle weakness and failure to thrive. A diagnosis of primary carnitine deficiency requires that serum, red cell and/or tissue carnitine levels be low and that the patient does not have a primary defect in fatty acid or organic acid oxidation (see Clinical Pharmacology ). In some patients, particularly those presenting with cardiomyopathy, carnitine supplementation rapidly alleviated signs and symptoms. Treatment should include, in addition to carnitine, supportive and other therapy as indicated by the condition of the patient.
CARNITOR(r) (Levocarnitine) is also indicated for acute and chronic treatment of patients with an inborn error of metabolism that results in a secondary carnitine deficiency.
Other indications : cardiomyopathy,chronic fatgue syndrome,obesity,intermittent claudication and oligospermia.
CONTRAINDICATIONS
None known.
WARNINGS
None.
PRECAUTIONS
General
CARNITOR(r) (Levocarnitine) Oral Solution is for oral/internal use only.
Not for parenteral use.
Gastrointestinal reactions may result from too rapid consumption of carnitine. CARNITOR(r) (Levocarnitine) Oral Solution may be consumed alone, or dissolved in drinks or other liquid foods to reduce taste fatigue. It should be consumed slowly and doses should be spaced evenly throughout the day to maximize tolerance.
Carcinogenesis, mutagenesis, impairment of fertility
Mutagenicity tests performed in Salmonella typhimurium, Saccharomyces cerevisiae, and Schizosaccharomyces pombe indicate that CARNITOR(r) (Levocarnitine) is not mutagenic. Long-term animal studies have not been conducted to evaluate the carcinogenicity of the compound.
Pregnancy
Pregnancy Category B.
Reproductive studies have been performed in rats and rabbits at doses up to 3.8 times the human dose on the basis of surface area and have revealed no evidence of impaired fertility or harm to the fetus due to CARNITOR(r). There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric use
See Dosage and Administration .
ADVERSE REACTIONS
Various mild gastrointestinal complaints have been reported during the long-term administration of oral L- or D,L-carnitine; these include transient nausea and vomiting, abdominal cramps, and diarrhea. Mild myasthenia has been described only in uremic patients receiving D,L-carnitine. Gastrointestinal adverse reactions with CARNITOR(r) (Levocarnitine) Oral Solution dissolved in liquids might be avoided by a slow consumption of the solution or by a greater dilution. Decreasing the dosage often diminishes or eliminates drug-related patient body odor or gastrointestinal symptoms when present. Tolerance should be monitored very closely during the first week of administration, and after any dosage increases.
Seizures have been reported to occur in patients with or without pre-existing seizure activity receiving either oral or intravenous levocarnitine. In patients with pre-existing seizure activity, an increase in seizure frequency and/or severity has been reported.
OVERDOSAGE
There have been no reports of toxicity from carnitine overdosage. The oral LD 50 of levocarnitine in mice is 19.2 g/kg. Carnitine may cause diarrhea. Overdosage should be treated with supportive care.
DOSAGE AND ADMINISTRATION
CARNITOR(r) (Levocarnitine) Tablets.
Adults: The recommended oral dosage for adults is 990 mg two or three times a day using the 330 mg tablets, depending on clinical response.
Infants and children: The recommended oral dosage for infants and children is between 50 and 100 mg/kg/day in divided doses, with a maximum of 3 g/day. Dosage should begin at 50 mg/kg/day. The exact dosage will depend on clinical response.
Monitoring should include periodic blood chemistries, vital signs, plasma carnitine concentrations and overall clinical condition.
CARNITOR(r) (Levocarnitine) Oral Solution.
For oral use only. Not for parenteral use.
Adults: The recommended dosage of levocarnitine is 1 to 3 g/day for a 50 kg subject, which is equivalent to 10 to 30 mL/day of CARNITOR(r) (Levocarnitine) Oral Solution. Higher doses should be administered only with caution and only where clinical and biochemical considerations make it seem likely that higher doses will be of benefit. Dosage should start at 1 g/day, (10 mL/day), and be increased slowly while assessing tolerance and therapeutic response. Monitoring should include periodic blood chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition.
Infants and children: The recommended dosage of levocarnitine is 50 to 100 mg/kg/day which is equivalent to 0.5 mL/kg/day CARNITOR(r) (Levocarnitine) Oral Solution. Higher doses should be administered only with caution and only where clinical and biochemical considerations make it seem likely that higher doses will be of benefit. Dosage should start at 50 mg/kg/day, and be increased slowly to a maximum of 3 g/day (30 mL/day) while assessing tolerance and therapeutic response. Monitoring should include periodic blood chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition.
CARNITOR(r) (Levocarnitine) Oral Solution may be consumed alone or dissolved in drink or other liquid food. Doses should be spaced evenly throughout the day (every three or four hours) preferably during or following meals and should be consumed slowly in order to maximize tolerance.
REFERENCES
Bohmer, T., Rydning, A., Solberg, H.E. 1974. Carnitine levels in human serum in health and disease. Clin. Chim. Acta 57:55-61.
Brooks, H., Goldberg, L., Holland R. et al. 1977. Carnitine-induced effects on cardiac and peripheral hemodynamics. J. Clin. Pharmacol. 17:561-568.
Christiansen, R., Bremer, J. 1976. Active transport of butyrobetaine and carnitine into isolated liver cells. Biochim. Biophys. Acta 448:562-577.
Lindstedt, S. and Lindstedt, G. 1961. Distribution and excretion of carnitine in the rat. Acta Chem. Scand. 15:701-702.
Rebouche, C.J. and Engel, A.G. 1983. Carnitine metabolism and deficiency syndromes. Mayo Clin. Proc. 58:533-540.
Rebouche, C.J. and Paulson, D.J. 1986. Carnitine metabolism and function in humans. Ann. Rev. Nutr. 6:41-66.
Scriver, C.R., Beaudet, A.L., Sly, W.S. and Valle, D. 1989. The Metabolic Basis of Inherited Disease . New York: McGraw-Hill.
Schaub, J., Van Hoof, F. and Vis, H.L. 1991. Inborn Errors of Metabolism. New York: Raven Press.
Marzo, A., Arrigoni Martelli, E., Mancinelli, A., Cardace, G., Corbelletta, C., Bassani, E. and Solbiati, M. 1991. Protein binding of L-carnitine family components. Eur. J. Drug Met. Pharmacokin., Special Issue III: 364-368.
Rebouche, C.J. 1991. Quantitative estimation of absorption and degradation of a carnitine supplement by human adults. Metabolism 40:1305-1310.