'N ondersoek na die moontlikheid om ' n trisikliese hokverbinding as ' n draermolekule vir die transport van karnitien oor selmembrane te gebruik.

Abstract

The importance of L-carnitine in the metabolism has long been a scientific fact. For certain individuals with a carnitine transport defect, the supplementation with carnitine is of life importance. The treatment of such patients includes the oral intake of a high dose of L-camitine. This approach assures that the residual transport activity of the defective carnitine transport protein (CTP), is maximally used to prevent intracellular carnitine levels from becoming depleted. This method of treatment however poses a few side effects. The aim of this study is to eva lu ate a possible alternative transport mechanism for carnitine, through which the intracellular L-camitine levels could possibly be in crease to such extend that normal activity can be rectified. Literature has shown that the uptake of a drug can be increased through the attachment of a macro molecular compound, which facilitates the transport. This lead to the chemical synthesis of adamantane carnitine conjugates through the joining of L-carnitine with tricyclic cage compounds namely 1-adamantane carboxylic acid, 1-adamantane acetic acid and 2-adamantadine. For the aim of this study vanous approaches will be followed. The first includes administering oral dosages of adamantane carnitine conjugates to experimental animals. For this purpose the Sprague Dawley rats was used. The presence of the conjugate as well as the free carnitine levels is determined in the blood and urine of the rats, which could give an indication of absorption, the degree of hydrolyses in the blood and the excretion through the urine. The second approach includes enzyme stability tests for each conjugate, through the use of an esterase enzyme. Finally the transport of the adamantane carnitine conjugate across cell membranes is determined. For this purpose fibroblast cells obtained from a patient suffering from a known inborn camitine transport protein defect is used. The effectiveness of the adamantane carnitine conjugates is determine through monitoring the fatty acid oxidation. Increased carnitine levels will Abstract J van Onselen 10802584 enhance I3-oxidation activity, which could serve as an indicator of successful transport of camitine via the adamantane camitine conjugate. After the successful synthesis of the adamantane camitine conjugates the results show a minimum to no increase in the free camitine or acetyl camitine levels in the blood and urine of the experimental animals after administration of the adamantane camitine conjugates. In most cases the concentrations remained constant or even decreased. The esterase enzyme stability analysis also showed few to no hydrolyses of the adamantane camitine conjugates. The transport study in fibroblast cell cultures showed a decrease in I3-oxidation activity. This indicates a decrease in free camitine levels, which highlights a possible transport inhibition. In conclusion the results is indicative of no potential usage of the adamantane camitine conjugates as treatment for patients with metabolic defects. On the contrary the conjugate has potential to be used as a model to study camitine transport defects