Alteration of Ammonia and Carnitine Levels in Short-Term Treatment with Pivalic Acid-Containing Prodrug.

Abstract

We investigated the influence on mitochondrial functions in carnitine deficiency caused by short-term treatment of cefterampivoxil (CFTM-PI) which is one of pivaloyloxymethyl-esterified antibiotics in adult volunteers and diseased children. Administration of CFTM-PI caused hypocarnitinemia in all cases, and we observed a significant elevation of blood ammonia levels compared with those after its withdrawal in diseased children. A significant negative correlation was found between the levels of serum free carnitine and blood ammonia, and a positive correlation was observed between serum carnitine and blood glutamine levels in all adult samples and samples during administration in diseased children. Our data suggest that these antibiotic medications affect the mitochondrial function even in a short-term treatment and that L-carnitine supplementation would be necessary for patients treated with CFTM-PI. carnitine deficiency; pivalic acid; hyperammonemia Carnitine, a cofactor for mitochondrial /l-oxidation of long-chain fatty acids, is essential for energy production and enhances the excretion of accumulated acyl-CoA to regulate the intramitochondrial CoA/acyl-CoA ratio. The systemic carnitine deficiency noted in various disorders can cause hypoketotic hypoglycemia, cardiomyopathy and Reye-like syndrome because functions of carnitine are insufficient.Some oral antibiotics in general use are esterified with pivaloyloxymethyl moiety in order to increase the intestinal absorption rate. This group of antibi-

Carnitine-related hypoglycemia caused by 3 days of pivalate antibiotic therapy in a patient with severe muscular dystrophy: a case report

“…However, a case has been reported of a 1-year-old Japanese patient with hypoglycemia associated with hypocarnitinemia induced by 2 days of cefcapene pivoxil treatment [12]. Additionally, Ito et al reported that treatment with cefteram pivoxil significantly decreased the level of serum free carnitine in both children and adults, even in short-term therapy, and advised that carnitine supplementation may be necessary for patients who are taking these antibiotics, particularly those vulnerable to carnitine deficiency [13]. Although our patient was an older child who could usually receive adequate calories orally (1200 kcal/day, appropriate for her body weight and activity level), she did not receive enough to eat for 3 days (about half of her usual calorific intake) after antibiotic treatment was initiated because of her acute pharyngitis.…”

Simultaneous quantification of acylcarnitine isomers containing dicarboxylic acylcarnitines in human serum and urine by high‐performance liquid chromatography/electrospray ionization tandem mass spectrometry

“…Valerylcarnitine (C5‐N) accumulates due to metabolic disorders involving fatty acids with odd‐numbered carbon chains, and 2‐methylbutyrylcarnitine (C5‐M) and isovalerylcarnitine (C5‐I) accumulate due to disorders involving isoleucine and leucine, respectively. Furthermore, pivaloylcarnitine (C5‐P) is formed when patients are treated with antibiotics modified by the pivoxyl group 7, 8. All these C5s are indistinguishable using the current MS/MS methodology.…”

Reducing the False-Positive Rate for Isovalerylcarnitine in Expanded Newborn Screening

“…The maximum C5-acylcarnitine blood concentration was reached 4 hours after balm ingestion in all volunteers. Considering that the pivalic acid derivative neopentanoic acid conjugates the free carnitine [4][5][6] and that the breast-feeding period could be quite long (generally some months), we cannot exclude a potentially dangerous secondary carnitine deficiency due to a long-term nipple fissure balm application. Exogenous unusual long-term pivalate exposure from pivalic esters of antibiotics to mothers or newborns had previously been reported as responsible for carnitine depletion and hypoglycemic convulsions.…”