Metabolism and disposition of intravenously administered acetyl-L-carnitine in healthy volunteers
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The pharmacokinetics of acetyl-L-carnitine hydrochloride were investigated in 6 healthy volunteers of both sexes after i.v. injection of 500 mg of the drug, expressed as inner salt.
Plasma concentrations and urinary excretion of acetyl-L-carnitine (A), L-carnitine (B) and total acid soluble L-carnitine fraction were evaluated over a period lasting from 24 h before to 48 h after the administration. Plasma concentrations of A increased quickly after administration and then declined reaching base values within 12 h.
Conversely, plasma concentrations of B rose more slowly, reaching a peak in 30–60 min, and then declined to base values within 24 h. Most of the injected dose of acetyl-L-carnitine was recovered in the urine during the first 24 h after administration as B and A.
Mean renal clearance of both A and B during the first 12 h after injection was higher than the base values, suggesting the presence of a saturable tubular reabsorption process which may counterbalance major changes occurring in plasma concentrations of L-carnitine pattern.
Key wordsacetyl-L-carnitine renal clearance pharmacokinetics healthy volunteers
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- 1.Bremer J (1962) Carnitine in intermediary metabolism. The metabolism of fatty acid esters of carnitine by mitochondria. J Biol Chem 237: 3628–3632Google Scholar
- 2.Fritz IB, Yue KTN (1963) Long-chain carnitine acyltransferase and the role of acylcarnitine derivatives in the catalytic increase of fatty acid oxidation induced by carnitine. J Lipid Res 4: 279–288Google Scholar
- 3.Lanoue KF, Schoolwerth AC (1979) Metabolite transport in the mitochondria. Ann Rev Biochem 48: 871–922Google Scholar
- 4.Pande SV, Parvin R (1976) Characterization of carnitine: Acylcarnitine translocase system of heart mitochondria. J Biol Chem 251: 6683–6691Google Scholar
- 5.Paulson DJ, Shug AL (1981) Tissue specific depletion of L-carnitine in rat heart and skeletal muscle by D-carnitine. Life Sci 28: 2931–2938Google Scholar
- 6.Boots MR, Wolfe ML, Boots SG, Bobbitt JL (1980) Effect of carnitine analogues on carnitine acetyltransferase. J Pharm Sci 69: 202–204Google Scholar
- 7.Fritz IB, Schultz SK (1965) Carnitine acetyltransferase. II Inhibition by carnitine analogues and by sulfhydryl reagents. J Biol Chem 240: 2188–2192Google Scholar
- 8.Cox RA, Hoppel CL (1973) Biosynthesis of carnitine and 4-N-trimethylamino butyrate from lysine. Biochem J 136: 1075–1082Google Scholar
- 9.Bremer J (1961) Biosynthesis of carnitine in vivo. Biochim Biophys Acta 48: 622–624Google Scholar
- 10.Haigler HT, Broquist HP (1974) Carnitine synthesis in rat tissue slices. Biochem Biophys Res Commun 56: 576–681Google Scholar
- 11.Böhmer T, Ryoning A, Solberg HE (1974) Carnitine levels in human serum in health and disease. Clin Chim Acta 57: 55–61Google Scholar
- 12.Engel AG, Angelini C (1973) Carnitine deficiency of human skeletal muscle with associated lipid storage myopathy: a new syndrome. Science 179: 899–902Google Scholar
- 13.Battistella PA, Angelini C, Vergani L, Bertoli M, Lorenzi A (1978) Carnitine deficiency induced during haemodialysis. Lancet 1: 938–939Google Scholar
- 14.Shung AL, Thomsen JH, Folts JD, Bittar N, Klein MI, Koke JR, Huth PJ (1978) Changes in tissue levels of carnitine and other metabolites during myocardial ischemia and anoxia. Arch Biochem Biophys 187: 25–33Google Scholar
- 15.Maebashi M, Sato M, Kawamura N, Imamura A, Yoshinaga K (1978) Lipid-lowering effects of carnitine in patients with type-IV hyperlipoproteinemia. Lancet 1: 805–807Google Scholar
- 16.Reed KW, Murray WJ, Roche EB (1980) Acetylcarnitine and cholinergic receptors. J Pharm Sci 69: 1065–1068Google Scholar
- 17.Sass RL, Werness P (1973) Acetylcarnitine: On the relationship between structure and function. Biochem Biophys Res Commun 55: 736–742Google Scholar
- 18.Fanelli O (1978) Carnitine and acetyl-carnitine, natural substances endowed with interesting pharmacological properties. Life Sci 23: 2563–2570Google Scholar
- 19.Bergamasco B, Tarenzi L, Leotta D, Scarsella L, Iannuccelli M, Bianco C (1985) Activity of acetyl-L-carnitine in primary degenerative dementia. IV World Congress of Biological Psychiatry, Philadelphia, USA, September 8–13Google Scholar
- 20.Martucci N, Agnoli A, Manna V (1986) Is acetyl-L-carnitine a cholinergic substance? In: Bes A, Calm J, Colm R, Hoyer S, Marc-Verques JP, Wisniewski HM (eds) Senile dementia: Early detection. John Libbey Ed., London, England, pp 401–407Google Scholar
- 21.Caraffa J, Fiori L, Meletani S, Maidoni S (1981) Valutazione dell'attività terapeutica della L-acetilcarnitina in pazienti affetti da dementia multiinfartuale. Lavoro Neuropsichiatrico 68: 1–12Google Scholar
- 22.Cederblad G, Lindsted S (1972) A method for the determination of carnitine in the picomol range. Clin Chim Acta 37: 235–243Google Scholar
- 23.Denis J, McGarry D, Foster DW (1976) An improved and simplified radioisotopic assay for the determination of free and esterified carnitine. J Lipid Res 17: 277–281Google Scholar
- 24.Pande SV, Caramancion MN (1981) A simple radioisotopic assay of acetylcarnitine and acetyl-CoA at picomolar levels. Anal Biochem 112: 30–38Google Scholar
- 25.Kirk RE (1982) Experimental design: Procedures for behavioural sciences, 2nd edn. Brooks-Cole, Belmont, CaliforniaGoogle Scholar
- 26.Rebouche CJ, Engel AG (1983) Kinetic compartmental analysis of carnitine metabolism in the dog. Arch Biochem Biophys 220: 60–70Google Scholar
- 27.Rebouche CJ, Engel AG (1984) Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. Evidence for alterations in tissue carnitine transport. J Clin Invest 73: 857–867Google Scholar
- 28.Rebouche CJ, Engel AG (1981) Primary systemic carnitine deficiency: I. Carnitine biosynthesis. Neurology 31: 813–818Google Scholar
- 29.Engel AG, Rebouche CJ, Wilson DM, Glasgow AM, Romshe CA, Cruse RP (1981) Primary systemic carnitine deficiency: II. Renal handling of carnitine. Neurology 31: 819–825Google Scholar
- 30.Uematsu T, Itaya T, Nishimoto M, Takiguchi V, Mizuno A, Nakashima M, Yoshinobu K, Hasebe T (1988) Pharmacokinetics and safety of L-carnitine infused i.v. in healthy subjects. Eur J Clin Pharmacol 34: 213–216Google Scholar