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Pivalate-generating prodrugs have been suggested to cause clinically significant hypocarnitinaemia. Tenofovir dipivoxil, a novel ester prodrug of tenofovir, can be used for treatment for hepatitis B and HIV infection and it was necessary to evaluate the effect of its treatment on carnitine homeostasis. We sought to investigate the effect of Class 1 drug tenofovir dipivoxil on endogenous L-carnitine level during a 72-hr test in healthy Chinese volunteers and to establish a suitable dose of L-carnitine nutritional supplement for patients who were administered short-term tenofovir dipivoxil tablets for treatment for hepatitis B and herpes simplex virus infection. Tenofovir dipivoxil was administered in one of eight dosing regimens (single dose 150, 300 and 600 mg, multiple dose 300, 450, and 600 mg, multiple dose 450 (600) mg tenofovir dipivoxil and 0.5 g L-carnitine) to gender-balanced groups of 84 healthy Chinese volunteers. Plasma concentrations of L-carnitine were quantified before, during and after treatment. Plasma L-carnitine concentrations fell during tenofovir dipivoxil dosing. The nadir in L-carnitine concentration was dependent on the dose of tenofovir dipivoxil and it decreased from 6.1 ± 0.6 to 4.4 ± 0.8 μg/ml, 6.1 ± 1.8 to 3.3 ± 1.2 μg/ml, 6.2 ± 0.6 to 2.5 ± 0.5 μg/ml for single doses of 150, 300, 600 mg tenofovir dipivoxil tablets and from 6.0 ± 1.4 to 2.1 ± 1.5 μg/ml, 6.2 ± 0.4 to 0.9 ± 0.5 μg/ml for multiple doses of 450, 600 mg tenofovir dipivoxil tablets, respectively. Short-term administration of tenofovir dipivoxil results in hypocarnitinaemia and increased losses of carnitine in resulting of minor adverse events of decreased food appetite, nausea, abdominal distention and muscle weakness. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Zinc supplementation is an important intervention against mortality from infectious disease. • Many patients using zinc supplementation will also be prescribed antimicrobials at some time. • Recently, an inhibitory effect of zinc on the absorption of β-lactam antibiotics has been demonstrated in animal studies, but there has been no clinical assessment of this drug-nutrient interaction. WHAT THIS STUDY ADDS • Zinc sulfate dosing significantly impaired the bioavailability and decreased T > MIC of cephalexin in healthy volunteers, which might lead to a clinical failure. • The dosing recommendation is that zinc sulfate can be safely administered 3 h after a cephalexin dose. AIMS To investigate the effect of zinc sulfate on pharmacokinetics of cephalexin when administered concurrently or at strategically spaced dosing times designed to avoid the potential interaction in healthy volunteers. METHODS In this study, all subjects ( n= 12) were randomized to receive the following four treatments, separated by a wash-out period of 7 days: cephalexin 500 mg alone, concomitantly with zinc 250 mg, 3 h after zinc 250 mg or 3 h before zinc 250 mg. RESULTS All subjects completed the study safely. Zinc supplements administered concurrently with cephalexin significantly decreased the peak serum concentration ( Cmax), area under the plasma concentration-time curve from zero to infinity (AUC0-∞) and the time for which the plasma concentration of the drug remained above the minimal inhibitory concentration of the pathogenic organism ( T > MIC) of cephalexin [mean percentage decrease (95% confidence intervals) of 31.05% (22.09-40.01%), 27.40% (18.33-36.47%) and 22.33% (12.51-32.16%), respectively; P < 0.05] compared with administration of cephalexin alone. Also, administration of zinc 3 h before cephalexin decreased the Cmax, AUC0-∞ and T > MIC of the drug compared with administration of cephalexin alone [mean percentage decrease (95% confidence intervals) of 11.48% (3.40-19.55%), 18.12% (9.63-26.60%) and 23.75% (14.30-33.20%), respectively; P < 0.05]. In contrast, the pharmacokinetics of cephalexin was not notably altered by administration of zinc 3 h after cephalexin dosing ( P > 0.05). CONCLUSIONS The significant interaction between zinc and cephalexin might affect the clinical outcome of cephalexin therapy. The dosing recommendation is that zinc sulfate can be safely administered 3 h after a cephalexin dose. [ABSTRACT FROM AUTHOR]