Effects of pivalic acid-containing prodrugs on carnitine homeostasis and on response to fasting in children

Abstract

Treatment of 17 children aged 2-9.5 years with a combination of pivmecillinam and pivampicillin (250-500 mumol 24 h-1) for more than 1 year resulted in a reduction of the free carnitine concentration in serum and muscle to less than 10% of the mean reference value. The decline in serum was slow, with an estimated half-life of about 5 months. Spontaneous replenishment occurred at about the same slow rate. Thus, there is no increase in endogenous carnitine synthesis as a response to increased demand of carnitine for detoxification. Supplementation with carnitine during treatment required at least a four-fold molar excess over pivalic acid to achieve and sustain a normal carnitine concentration. The replenishment of carnitine occurred with a half-life of 1.1-3.0 months. From determination of muscle-carnitine concentration in patients treated with pivaloyl-containing antibiotics and in patients with organic aciduris, we conclude that serum carnitine is a good predictor of carnitine stores in the body. Six non-supplemented patients with a serum free-carnitine concentration of 0.7-2.6 mumol l-1 had an inadequate ketone-body increase during a 24-h fast. Vomiting, nausea and tiredness occurred in three cases following the fasting period. After normalization of the serum-carnitine concentration, a normal response to fasting was observed. Thus, in some organic acidurias, for example medium-chain acyl-CoA dehydrogenase deficiency, a low liver concentration of carnitine may be an important contributing factor to hypoglycaemic and Reye-like attacks. We believe that prodrugs which contain pivalic acid should be avoided if acceptable alternatives exist. If used, supplementation with at least four-fold molar excess of carnitine is advisable.

Disposition of S-1108, a new oral cephem antibiotic, and metabolic fate of pivalic acid liberated from [pivaloyl-14C]S-1108 in rats and dogs

“…Furthermore, the formation of pivaloylcarnitine following pivampicillin administration has been reported (15,16). Despite the strong attention focused on the effect of pivalic acid on the carnitine level (2,9,10,15,16), there have been no reports about the general disposition of pivalic acid in relation to its safety and toxicity characteristics.…”

“…C]pivaloylglycine and [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]pivaloylcarnitine hydrochloride were synthesized by a reaction of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]pivaloylchloride with glycine and carnitine, respectively, as illustrated in Fig. 2.…”

Detection of Pivaloylcarnitine in Pediatric Patients with Hypocarnitinemia after Long-Term Administration of Pivalate-Containing Antibiotics

“…Holme et al (1992) reported long-term adverse effects of pivalate-containing antibiotics in children, including low muscle carnitine levels. In both of our patients, antibiotics containing pivalate were administered for very long periods of time.…”

“…A decrease in serum carnitine levels has been observed after short-term administration of prodrugs containing pivalate; however, short-term administration is considered safe because the carnitine stored in muscles is believed to be sufficient to maintain the tissue carnitine levels (Brass et al 2003). In contrast, long-term administration of prodrugs containing pivalate can cause hypoketotic hypoglycemia, convulsion, tiredness, behavioral problems and weakness in children (Holme et al 1992;Makino et al 2007).…”

Renal Handling of Carnitine in Secondary Carnitine Deficiency Disorders

“…There is little evidence for this postulate. Reported tissue values in these disorders are considerably higher than in the carnitine transport defect or with pivalate administration (2,7,10). One report indicates that the degree of free carnitine deficiency associated with PA and MMA is not severe enough to impair hepatic fatty acid oxidation (28).…”