TY - JOUR

T1 - Clarithromycin, trimethoprim, and penicillin and oxidative nucleic acid modifications in humans

T2 - randomised, controlled trials

AU - Larsen, Emil List

AU - Cejvanovic, Vanja

AU - Kjær, Laura Kofoed

AU - Pedersen, Morten Thorup

AU - Popik, Sara Daugaard

AU - Hansen, Lina Kallehave

AU - Andersen, Jon Thor Trærup

AU - Solem, Espen Victor Jimenez

AU - Broedbaek, Kasper

AU - Petersen, Morten

AU - Weimann, Allan

AU - Henriksen, Trine

AU - Lykkesfeldt, Jens

AU - Torp-Pedersen, Christian

AU - Poulsen, Henrik Enghusen

PY - 2017/8

Y1 - 2017/8

N2 - AimsIn vitro studies have demonstrated that formation of reactive oxygen species (ROS) contributes to the effect of bactericidal antibiotics. The formation of ROS is not restricted to bacteria, but also occurs in mammalian cells. Oxidative stress is linked to several diseases. This study investigates whether antibiotic drugs induce oxidative stress in healthy humans as a possible mechanism for adverse reactions to the antibiotic drugs.MethodsThis study contains information from two randomised, controlled trials. Participants underwent 1 week treatment with clarithromycin, trimethoprim, phenoxymethylpenicillin (penicillin V), or placebo. Oxidative modifications were measured as 24-h urinary excretion of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), and plasma levels of malondialdehyde before and after treatment as a measurement of DNA oxidation, RNA oxidation, and lipid peroxidation, respectively.ResultsClarithromycin significantly increased urinary excretion of 8-oxodG by 22.0% (95% confidence interval (CI): 3.6–40.4%) and 8-oxoGuo by 14.9% (95% CI: 3.7–26.1%). Further, we demonstrated that trimethoprim significantly lowered urinary excretion of 8-oxodG by 21.7% (95% CI: 5.8–37.6%), but did not influence urinary excretion of 8-oxoGuo. Penicillin V did not influence urinary excretion of 8-oxodG or 8-oxoGuo. None of the antibiotic drugs influenced plasma levels of malondialdehyde.ConclusionClarithromycin significantly increases oxidative nucleic acid modifications. Increased oxidative modifications might explain some of clarithromycin's known adverse reactions. Trimethoprim significantly lowers DNA oxidation but not RNA oxidation. Penicillin V had no effect on oxidative nucleic acid modifications.

AB - AimsIn vitro studies have demonstrated that formation of reactive oxygen species (ROS) contributes to the effect of bactericidal antibiotics. The formation of ROS is not restricted to bacteria, but also occurs in mammalian cells. Oxidative stress is linked to several diseases. This study investigates whether antibiotic drugs induce oxidative stress in healthy humans as a possible mechanism for adverse reactions to the antibiotic drugs.MethodsThis study contains information from two randomised, controlled trials. Participants underwent 1 week treatment with clarithromycin, trimethoprim, phenoxymethylpenicillin (penicillin V), or placebo. Oxidative modifications were measured as 24-h urinary excretion of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), and plasma levels of malondialdehyde before and after treatment as a measurement of DNA oxidation, RNA oxidation, and lipid peroxidation, respectively.ResultsClarithromycin significantly increased urinary excretion of 8-oxodG by 22.0% (95% confidence interval (CI): 3.6–40.4%) and 8-oxoGuo by 14.9% (95% CI: 3.7–26.1%). Further, we demonstrated that trimethoprim significantly lowered urinary excretion of 8-oxodG by 21.7% (95% CI: 5.8–37.6%), but did not influence urinary excretion of 8-oxoGuo. Penicillin V did not influence urinary excretion of 8-oxodG or 8-oxoGuo. None of the antibiotic drugs influenced plasma levels of malondialdehyde.ConclusionClarithromycin significantly increases oxidative nucleic acid modifications. Increased oxidative modifications might explain some of clarithromycin's known adverse reactions. Trimethoprim significantly lowers DNA oxidation but not RNA oxidation. Penicillin V had no effect on oxidative nucleic acid modifications.

KW - antibiotics

KW - oxidative stress

KW - 8-oxo-7

KW - 8-dihydro-2-deoxyguanosine

KW - 8-dihydroguanosine

KW - DNA oxidation

KW - RNA oxidation

U2 - 10.1111/bcp.13261

DO - 10.1111/bcp.13261

M3 - Journal article

C2 - 28185274

VL - 83

SP - 1643

EP - 1653

JO - British Journal of Clinical Pharmacology, Supplement

JF - British Journal of Clinical Pharmacology, Supplement

SN - 0264-3774

IS - 8

ER -