Organic acids, Cerebrospinal fluid

Numerous studies have been published on the in vivo metabolism of peptides. However, these studies are concerned mainly with assessment of pharmacokinetic parameters such as half-life and clearance. Only seldom is the in vivo biotransformation of peptides that contain only common amino acids investigated in any detail, due to the difficulty of monitoring products of proteolysis that are identical to endogenous peptides and amino acids. More importantly, such studies fail to yield mechanistic and biochemical insights. For this reason, we begin here with a discussion of the metabolism of just a few peptides in some selected tissues, namely portals of entry (mouth, gastro-intestinal tract, nose, and skin), plasma, organs of elimination (liver, kidney), and pharmacodynamic sites (brain and cerebrospinal fluid). These examples serve as introduction for the presentation in Sect. 6.4.2 of the involvement of individual peptidases in peptide metabolism. 

Biotinidase activity in cerebrospinal fluid and the brain is very low. This suggests that the brain may not recycle biotin effectively and depends on biotin transported across the blood-brain barrier. Several symptomatic children who have failed to exhibit peripheral lactic acidosis or organic aciduria have had elevated lactate or organic acids in their cerebrospinal fluid. This compartmentalization of the biochemical abnormalities may explain why the neurological symptoms usually appear before other symptoms. Peripheral metabolic ketoacidosis and organic aciduria subsequently occur with prolonged metabolic compromise. 

Body fluids other than urine have considerably less complex low-molecular-weight component spectrums, at least at the concentration levels that can be detected by these analyzers. For example, blood serum samples, when compared with urine, will have about one-fourth as many chromatographic peaks of UV-absorbing constituents and carbohydrates and about one-half as many ninhydrin-positive and organic acid chromatographic peaks. Cerebrospinal fluid appears to have about the same complexity in UV-absorbing and carbohydrate components as does blood serum, and perspiration falls somewhere between urine and serum. 

The unbound drug in the systemic circulation is available to distribute extravascularly. The extent of distribution is mainly determined by lipid solubility and, for weak organic acids and bases, is influenced by the pK3/pH-dependent degree of ionization because only the more lipid-soluble non-ionized form can passively diffuse through cell membranes and penetrate cellular barriers such as those which separate blood from transcellular fluids (cerebrospinal and synovial fluids and aqueous humour). The milk-to-plasma equilibrium concentration ratio of an antimicrobial agent provides a reasonably... 

Patients with folate deficiency and organic mental changes, polyneuropathy, and depression have been found to have a reduced cerebrospinal fluid level of 5-hydroxyindoleacetic acid. Following treatment with the vitamin the 5-hydroxyindoleacetic acid level was found to return to normal in those patients who showed improvement in their neuropsychiatric signs. However, patients who were folate deficient with neuropsychiatric symptoms which were not responsive to treatment with folic acid showed no change in their level of cerebrospinal 5-hydroxyindoleacetic acid (BIT). 

Cerebrospinal Fluid PeniciUin does not readily enter the CSF but penetrates more easily with meningeal inflammation. The concentration attained usuaUy reaches 5% of the value in plasma and thus is therapeutically effective against susceptible microorganisms. Penicilhn and other organic acids are secreted rapidly from the CSF into the bloodstream by an active transport process. In uremia, other organic acids compete with penicillin for secretion the drug occasionally reaches toxic CNS concentrations that can produce convulsions. 

Hiraoka, A., Akai, J., Tominaga, L, Hattori, M., Sasaki, H., and Arato, T. Capillary zone electrophoretic determination of organic acids in cerebrospinal fluid frompatients with central nervous system diseases. J. Chromatogr. A, 680, 243, 1994. 

Gas Chromatography-Mass Spectrometric Analysis of Organic Acids in Human Cerebrospinal Fluid Koensju - lyo Masu Kenfcy ukai 4 289-292 (1979) CA 92 193769p... 

Coude M, Kamoun P (1992) Organic acids in post-mortem cerebrospinal fluid. Clin Chim Acta 206 201-206... 

Hoffmann GF, Meier-Augenstein W, Stockier S, Surtees R, Rating D, Nyhan WL (1993) Physiology and pathophysiology of organic acids in cerebrospinal fluid. J Inher Metab Dis 16 648-669... 

Since most organic acids undergo efficient renal excretion and urine is often obtained more easily from children than other body fluids, urine represents the preferred sample for organic acid analysis. However, in special cases or if no other sample should be available, plasma, serum, cerebrospinal fluid, or vitreous... 

Organic acids in physiological fluids from normal subjects H.2 Cerebrospinal fluid... 

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