Effects of pivalic acid-containing prodrugs on carnitine homeostasis and on response to fasting in children.
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.
Holme
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E
Department of Clinical Chemistry, Gothenburg University, Sahlgren's Hospital, Sweden.
Jodal
U
U
Linstedt
S
S
Nordin
I
I
D000561:Amdinocillin Pivoxil / Q000008:administration & dosage / Q000009:adverse effects*; D002331:Carnitine / Q000172:deficiency* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005215:Fasting / Q000502:physiology*; D005260:Female; D006706:Homeostasis; D006801:Humans; D009132:Muscles / Q000378:metabolism; D010421:Pentanoic Acids / Q000009:adverse effects*; D010917:Pivampicillin / Q000008:administration & dosage / Q000009:adverse effects*; D011355:Prodrugs / Q000009:adverse effects*; D012016:Reference Values
D010421:Pentanoic Acids; D011355:Prodrugs; D010917:Pivampicillin; D000561:Amdinocillin Pivoxil; C005566:pivalic acid; D002331:Carnitine