Carnitine excretion

Cefditoren Cefditoren is contraindicated in patients with carnitine deficiency or inborn errors of metabolism that may result in clinically significant carnitine deficiency because use of cefditoren causes renal excretion of carnitine. 

Carnitine, L-3-hydroxy-4-(trimethylammonium)butyrate, is a water-soluble, tri-methylammonium derivative of y-amino-jS-hydroxybutyric acid, which is formed from trimethyllysine via y-butyrobetaine [40]. About 75% of carnitine is obtained from dietary intake of meat, fish, and dairy products containing proteins with trimethyllysine residues. Under normal conditions, endogenous synthesis from lysine and methionine plays a minor role, but can be stimulated by a diet low in carnitine. Carnitine is not further metabolized and is excreted in urine and bile as free carnitine or as conjugated carnitine esters [1, 41, 42]. Adequate intracellular levels of carnitine are therefore maintained by mechanisms that modulate dietary intake, endogenous synthesis, reabsorption, and cellular uptake. 

Chalmers RA, Roe CR, Stacey , Hoppel CL (1988) Urinary excretion of L-carnitine and acylcarnitines by patients with disorders of organic acid metabolism evidence for secondary insufficiency of L-carnitine. Pediatr Res 18 1325-1328... 

Roe CR, Millington DS, Maltby DA, Bohan TP, Hoppel CL (1984) L-carnitine enhances excretion of propionyl coenzyme A as propionylcarnitine in propionic acidemia. J Clin Invest 73 1785-1788... 

Normal persons excrete very little TMA in the urine. However, slight TMA excretion may be observed after meals with a high content of TMA precursors like choline or lecithin, or after eating marine fish due to its high TMA N-oxide content. Healthy women may have a short episode of trimethylaminuria at the onset and during menstruation. TMA has also found to be increased in the urine of some patients using carnitine supplementation. Advanced liver and renal disease may result in TMA excretion and this constitutes the so-called secondary trimethylaminurias. 

One of the most frequent defects of fatty acid oxidation is deficiency of a mitochondrial acyl-CoA dehydrogenase.50 If the long-chain-specific enzyme is lacking, the rate of P oxidation of such substrates as octanoate is much less than normal and afflicted individuals excrete in their urine hexanedioic (adipic), octanedioic, and decanedioic acids, all products of co oxidation.54 Much more common is the lack of the mitochondrial medium-chain acyl-CoA dehydrogenase. Again, dicarboxylic acids, which are presumably generated by 0) oxidation in the peroxisomes, are present in blood and urine. Patients must avoid fasting and may benefit from extra carnitine. 

Melegh B, Kerner J, Jaszai V, Bieber L. Differential excretion of xenobiotic acylesters of carnitine due to administration of pivampicillin and valproate. Biochem Med Metabol Biol 1990 43 30-8. 

Supplementing the diet with carnitine may stimulate the uptake of long-chain fatty acids into affected cells. Fatty acid oxidation within the mitochondrion will generate acetyl-CoA, which when oxidized in the TCA cycle will produce NADH and FADH2 to feed into the ETC. Carnitine also shuttles potentially toxic fatty acid catabolic by-products out of the mitochondrial matrix to the kidney for excretion in the urine. 

Carnitine deficiency complicates HMG-CoA lyase deficiency and other inborn errors of metabolism, which results in organic acidemia. L-Camitine or P-hydroxy-y-trimethylammonium butyrate is a carrier molecule that transports long-chain fatty acids across the inner mitochondrial membrane for subsequent P-oxi-dation. L-Carnitine also facilitates removal of toxic metabolic intermediates or xenobiotics via urinary excretion of their acyl carnitine derivatives. Indeed, individuals with HMG-CoA lyase deficiency have been shown to excrete 3-methylgluatarylcamitine (Roe et al., 1986). In the absence of ketogenesis, the formation of the acyl carnitine derivative of 3-hydroxy-3-methylglutarate from HMG-CoA also serves to regenerate free CoA in the mitochondria and permits continued P-oxidation of fatty acids. 

As a result of the reduced activity of the mutase in vitamin B12 deficiency, there is an accumulation of methyhnalonyl CoA, some of which is hydrolyzed to yield methylmalonic acid, which is excreted in the urine. As discussed in Section 10.10.3, this can be exploited as a means of assessing vitamin B12 nutritional status. There may also be some general metabolic acidosis, which has been attributed to depletion of CoA because of the accumulation of methyl-malonyl CoA. However, vitamin B12 deficiency seems to result in increased synthesis of CoA to maintain normal pools of metabolically useable coenzyme. Unlike coenzyme A and acetyl CoA, neither methylmalonyl CoA nor propionyl CoA (which also accumulates in vitamin B12 deficiency) inhibits pantothenate kinase (Section 12.2.1). Thus, as CoA is sequestered in these metabolic intermediates, there is relief of feedback inhibition of its de novo synthesis. At the same time, CoA may be spared by the formation of short-chain fatty acyl carnitine derivatives (Section 14.1.1), which are excreted in increased amounts in vitamin B12 deficiency. In vitamin Bi2-deficient rats, the urinary excretion of acyl carnitine increases from 10 to 11 nmol per day to 120nmolper day (Brass etal., 1990). 

The major functions of pantothenic acid are in CoA (Section 12.2.1) and as the prosthetic group for AGP in fatty acid synthesis (Section 12.2.3). In addition to its role in fatty acid oxidation, CoA is the major carrier of acyl groups for a wide variety of acyl transfer reactions. It is noteworthy that a wide variety of metabolic diseases in which there is defective metabolism of an acyl CoA derivative (e.g., the biotin-dependent carboxylase deficiencies Sections 11.2.2.1 and 11.2.3.1), CoA is spared by formation and excretion of acyl carnitine derivatives, possibly to such an extent that the capacity to synthesize carnitine is exceeded, resulting in functional carnitine deficiency (Section 14.1.2). 

The total body content of carnitine is about 100 mmol, and about 5% of this turns over daily. Plasma total carnitine is between 36 to 83 /rmol per L in men and 28 to 75 /rmol per L in women, mainly as free carnitine. Although both free carnitine and acyl carnitine esters are excreted in the urine, much is oxidized to trimethylamine and trimethylamine oxide. It is not known whether the formation of trimethylamine and trimethylamine oxide is caused by endogenous enzymes or intestinal bacterial metabolism of carnitine. 

Total urinary excretion of carnitine is between 300 to 530 /rmol (men) or 200 to 320 /rmol (women) 30% to 50% of this is free carnitine the remainder is a variety of acyl carnitine esters. Acyl carnitine esters are readily cleared in... 

Urinary excretion of acyl carnitine esters increases considerably in a variety of conditions involving organic aciduria carnitine acts to spare CoA and pantothenic acid (Section 12.2), by releasing the coenzyme from otherwise nonmetabolizable esters that would trap the coenzyme and cause functional pantothenic acid deficiency. 

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