Carnitine esterified

After uptake by the liver, free fatty acids are either P Oxidized to COj or ketone bodies or esterified to triacylglycerol and phospholipid. There is regulation of entry of fatty acids into the oxidative pathway by carnitine palmitojdtransferase-I (CPT-I), and the remainder of the fatty acid uptake is esterified. CPT-I activity is... 

Adefovir dipivoxil is well tolerated. A dose-dependent nephrotoxicity has been observed in clinical trials, manifested by increased serum creatinine with decreased serum phosphorous and more common in patients with baseline renal insufficiency and those receiving high doses (60 mg/d). Other potential adverse effects are headache, diarrhea, asthenia, and abdominal pain. As with other NRTI agents, lactic acidosis and hepatic steatosis are considered a risk owing to mitochondrial dysfunction. No clinically important drug-drug interactions have been recognized to date. Pivalic acid, a by-product of adefovir dipivoxil metabolism, can esterify free carnitine and result in decreased carnitine levels. However, it is not felt necessary to administer carnitine supplementation with the low doses used to treat patients with HBV (10 mg/d). 

Under physiologic conditions, carnitine is primarily required to shuttle long-chain fatty acids across the inner mitochondrial membrane for FAO and products of peroxisomal /1-oxidation to the mitochondria for further metabolism in the citric acid cycle [40, 43]. Acylcarnitines are formed by conjugating acyl-CoA moieties to carnitine, which in the case of activated long-chain fatty acids is accomplished by CPT type I (CPT-I) [8, 44]. The acyl-group of the activated fatty acid (fatty acyl-CoA) is transferred by CPT-I from the sulfur atom of CoA to the hydroxyl group of carnitine (Fig. 3.2.1). Carnitine acylcarnitine translocase (CACT) then transfers the long-chain acylcarnitines across the inner mitochondrial membrane, where CPT-II reverses the action of CPT-I by the formation of acyl-CoA and release of free un-esterified carnitine. 

Although possible interference with the metabolism of carnitine by pivaloylmethyl-esterified beta-lactams is a matter of concern (SEDA-21, 260), new similar prodrug derivatives of cephalosporins continue to be marketed, as do reports that they can be given to healthy volunteers without concern (42). 

The mitochondrial inner membrane is impermeable to fatty acyl-CoA. To be transported into mitochondria, the acyl moiety must first be esterified to L-carnitine (hereafter referred to simply as carnitine) to form the corresponding fatty acylcarnitine. This reaction is catalyzed by carnitine palmitoyltransferase I (CPTI) localized... 

Carnitine is required for transport of longoxidative metabolism as well as in the formation of ketone bcidies, The concentration of free carnitine in muscle is about 4,0 mmol/kg. The concentration of carnitine bound to long-chain fatty adds (fatty acyl-camitine) is lower, about 0,2 mmol/kg. Short-chain fatty adds, including acetic, are also esterified to carnitine, but the functions of these complexes are not clear. There is some indication that keto forms of BCAAs (BCKAs) can also be esterified to carnitine. These complexes can then be transported into the mitochondria for complete oxidation of the BCKAs, The importance of this mode of BCKA transport is not dear (Takakura et ai., 1997). 

Carnitine tablets are sold in health food stores. It is claimed that carnitine will enhance the breakdown of body fat. Carnitine is a tertiary amine found in mitochondria, cell organelles in which food molecules are completely oxidized and ATP is produced. Carnitine is involved in transporting the acyl groups of fatty acids from the cytoplasm into the mitochondria. The fatty acyl group is transferred from a fatty acyl CoA molecule and esterified to carnitine. Inside the mitochondria the reachon is reversed and the fatty acid is completely oxidized. The structure of carnitine is shown here ... 

Acyl groups are esterified to carnitine to cross the inner mitochondrial membrane. There are transesterification reactions from the acyl-CoA to carnitine and from acylcarnitine to CoA (see Figure 21.5). 

McGarry, J.D. Foster, D.W. (1976) J. Lipid Res. 17, 277-281. An improved and simplified radioisotopic assay for the determination of free and esterified carnitine. 

The carnitine profile quantifies the amount of carnitine present (total carnitine) as well as the carnitine that is free or bound by an ester link to acyl-CoA (acyl or esterified carnitine) (Box 8.2). 

Most patients with PROP and MMA are prescribed L-camitine supplements to prevent a secondary carnitine deficiency, and routine measurement of plasma or serum carnitine is recommended [5]. This analysis will include total carnitine, carnitine esters (esterified), and free carnitine concentrations. Low concentrations of free carnitine suggest a need to increase the supplementation dose. With supplementation, the total and ester fractions are often elevated. 

Plasma carnitine profile (total, esterified, free)... 

After transport across the plasma membrane, FAs must be esterified to coenzyme A, on the outer mitochodrial membrane by long chain acyl-CoA synthetase activity (ACSL C12 to C20) before they can undergo oxidative degradation. This reaction is coupled with two ATP hydrolysis to AMP and 2Pi. The mitochondrial membrane is not permeable to long chain acyl-CoA (i.e., C16-C18), therefore requires the initial conversion of acyl-CoA to an ester acylcamitine, followed by transport of the acylcamitine across the inner mitochondrial membrane into the mitochondrial matrix and subsequent delivery of acyl-CoA [126], This process is referred to as carnitine shuttle and requires the concerted action of 3 proteins 6 ... 

Metabolism—Like the water-soluble vitamins, it is believed that carnitine is easily and rather completely absorbed. However, the form of carnitine (free or esterified) which is absorbed, the exact mechanism of absorption... 

Carnitine serves as a cofactor for several enzymes, including carnitine translo-case and acyl carnitine transferases I and II, which are essential for the movement of activated long-chain fatty acids from the cytoplasm into the mitochondria (Figure 11.2). The translocation of fatty acids (FAs) is critical for the genaation of adenosine triphosphate (ATP) within skeletal muscle, via 3-oxidation. These activated FAs become esterified to acylcamitines with carnitine via camitine-acyl-transferase I (CAT I) in the outer mitochondrial membrane. Acylcamitines can easily permeate the membrane of the mitochondria and are translocated across the membrane by carnitine translocase. Carnitine s actions are not yet complete because the mitochondrion has two membranes to cross thus, through the action of CAT II, the acylcar-nitines are converted back to acyl-CoA and carnitine. Acyl-CoA can be used to generate ATP via 3-oxidation, Krebs cycle, and the electron transport chain. Carnitine is recycled to the cytoplasm for fumre use. 

In general, carnitine homeostasis is maintained several ways, ineluding absorption from dietary sources, modest rates of biosynthesis, and reabsorption, which is very efficient. Carnitine in its esterified forms as short- and long-ehain aeylcanutines is found in several tissues and cellular fluid. In a healthy 70-kg adult the pool of... 

Frolich, J., Seccombe, D.W., and Hahn, R, Effect of fasting on free and esterified carnitine levels in human serum and urine correlation with serum levels of free fatty acids and (i-hydroxybutyrate. Metabolism, 27, 555-561, 1978. 

Several diseases are known that result in elevations in tissues and fluids of various esters of carnitine and reduce the availability of free carnitine, which is normally synthesized by humans and is necessary for the transport of long-chain fatty acids into mitochondria for oxidation. In several disorders arising from acyl-CoA dehydrogenase deficiencies, the accumulation of the acyl-CoA substrate frequently sequesters coenzyme A and reduces its availability for other unrelated but important and otherwise competent pathways. Carnitine administration can displace and make available much of the coenzyme A that had been isolated, and stimulate the excretion of the accumulating acidic metabolites now esterified to carnitine. Detection of reduced levels of serum or urinary free carnitine and elevations of esterified carnitine is therefore useful for diagnosis of a variety of metabolic disorders, among them congenital inability to synthesize carnitine. In this disorder, carnitine must be supplied by a carnitine-enriched diet as it is, in effect, a vitamin. 

---