Impact on carnitine homeostasis of short-term treatment with the pivalate prodrug cefditoren pivoxil

Abstract

Short-term administration of cefditoren pivoxil results in hypocarnitinemia and increased net losses of total carnitine. It is estimated that net carnitine losses were only 10% of body stores, even with the highest dose regimen tested. Losses of this magnitude would not be anticipated to result in adverse clinical effects.

Carnitine: a nutritional, biosynthetic, and functional perspective

“…Instead the acyl group is transferred to carnitine forming pivaloylcarnitine which leaves the tissue and is eliminated in the urine. In humans, over 90% of the administered pivalic acid is eliminated from the body in form of pivaloylcarnitine (Vickers et al, 1985;Melegh et al, 1987;Brass et al, 2003). Long-term treatment with pivaloyloxyethyl or pivaloyloxymethyl containing prodrugs leads to elevated and sustained excretion of (pivaloyl)carnitine and may lead to secondary carnitine deficiency (Holme et al, 1989).…”

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

“…Side effects of pivalate-containing antibiotics are described in more detail elsewhere, but some of these effects include hypocarnitinemia and hypoketotic hypoglycemia (Holme et al 1989;Brass et al 2003). In fact, the effects of free pivalate and pivaloyl-CoA are rarely observed because they only develop after the tissue carnitine reserves are exhausted.…”

“…After antibiotic administration, the pivalate molecule is converted to pivaloylcarnitine and is excreted in the urine (Holme et al 1989). 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).…”

Impact on L‐carnitine Homeostasis of Short‐term Treatment with the Pivalate Prodrug Tenofovir Dipivoxil

“…The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism and excretion (ADME) optimization. Prodrugs are usually designed to improve oral bioavailability, with poor absorption from the gastrointestinal tract usually being the limiting factor [2].Tenofovir dipivoxil, a novel ester prodrug of tenofovir, is an orally administered nucleotide analogue reverse transcriptase inhibitor (ntRTI) and can be used for treatment for hepatitis B and human immunodeficiency virus (HIV) infection. According to our phase I clinical trials, the relative bioavailability of tenofovir dipivoxil was improved about 20% higher compared with tenofovir disoproxil fumarate [3].…”

“…The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism and excretion (ADME) optimization. Prodrugs are usually designed to improve oral bioavailability, with poor absorption from the gastrointestinal tract usually being the limiting factor [2].…”