Biochemical rationale for the use of CDPcholine in traumatic brain injury: pharmacokinetics of the orally administered drug.
A pharmacokinetic analysis of CDPcholine has been carried out treating either rats or dogs by oral administration with the double labelled molecule. [methyl-14C,5-3H]CDPcholine represents a useful tool to test the structural integrity of this compound during the transmembrane transport and to follow the metabolic fate of cytidine and choline fragments. Furthermore, the identification of the labelled metabolites of the exogenously administered CDPcholine in the various organs allows us to draw inferences about its pharmacological mechanism(s). These studies appear of great interest in view of the extensive therapeutic use of the molecule in the treatment of several CNS pathologies including traumatic brain injury. The results of this work can be summarized as follows. (a) The molecule is rapidly cleaved at the level of the pyrophosphate bridge and a fast uptake of the hydrolytic products occurs. (b) The metabolism of the molecule is characterized by a differential utilization of the two moieties by the various organs. Liver is the most active organ in utilizing CDPcholine with a preferential uptake of the choline fragment. (c) The [3H]cytidine moiety, in all the organs examined, appears to be incorporated into the nucleic acid fraction via the cytidine nucleotide pool. The [14C]choline moiety is in part converted into betaine, which in turn acts as methyl donor to homocysteine, yielding [14C]methionine, subsequently incorporated into proteins. The time-dependent increase in the labelling of phospholipids is indicative of a recycling of choline methyl groups via CDPcholine and/or S-adenosylmethionine. (d) The uptake of CDPcholine by the brain is relatively low; however, a good metabolic utilization of the drug can be observed.(ABSTRACT TRUNCATED AT 250 WORDS)
Galletti
P
P
Department of Biochemistry of Macromolecules, I Medical School, University of Naples, Italy.
De Rosa
M
M
Cotticelli
M G
MG
Morana
A
A
Vaccaro
R
R
Zappia
V
V
D000284:Administration, Oral; D000818:Animals; D001930:Brain Injuries / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D003566:Cytidine Diphosphate Choline / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004285:Dogs; D005260:Female; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014316:Tritium
D002250:Carbon Radioisotopes; D014316:Tritium; D003566:Cytidine Diphosphate Choline