Clinical pharmacokinetics of metronidazole and other nitroimidazole anti-infectives.

Metronidazole was first introduced for the treatment of trichomoniasis. Its therapeutic use has subsequently been expanded to include amoebiasis, giardiasis and, more recently, anaerobic infections. Most of the early pharmacokinetic studies employed nonspecific assays such as microbiological and chemical assays. These assays were not able to differentiate the parent drug from the metabolites or other interfering substances. Pharmacokinetic data obtained through the use of specific Chromatographic techniques provide the basis for this review of recent pharmacokinetic findings concerning metronidazole and other nitroimidazole antibiotics. When given intravenously or orally at usual recommended doses, metronidazole attains concentrations well above the minimum inhibitory concentrations for most susceptible micro-organisms. The drug has an oral bioavailability approaching 100%. Rectal and vaginal administration results in a smaller amount of drug absorption and lower serum concentrations. Metronidazole has limited plasma protein binding but can attain very favourable tissue distribution, including into the central nervous system. The drug is extensively metabolised by the liver to form 2 primary oxidative metabolites: the hydroxy and acetic acid metabolites. The kidney is responsible for the elimination of only a small amount of the parent drug; however, normal excretion of the 2 metabolites is dependent on the integrity of kidney function. The metabolism of metronidazole was found to vary among patient groups. Preterm and term infants have lower total body clearance (CL) and prolonged elimination half-lives. However, children older than 4 years old were observed to have pharmacokinetic parameters similar to those in adults. Reduced CL was also observed in children who are malnourished. Elderly patients have reduced renal excretion of both the parent drug and hydroxy metabolite. Pharmacokinetic parameters in pregnant patients were not significantly different from those in nonpregnant women; however, the drug is distributed into breastmilk and the infant will be exposed to the drug through the nursing mother. Patients undergoing gastrointestinal surgery or having enteric diseases and those who are hospitalised or critically ill also have altered pharmacokinetics. Metabolism of the drug is reduced in patients with liver dysfunction, giving delayed production of metabolites. In contrast, renal failure has little effect on the elimination of the parent drug, but affects the excretion of the metabolites more significantly. Haemodialysis was found to remove a substantial amount of the metronidazole while the effect of peritoneal dialysis was more limited. Energy and protein deficient diets as well as occupational exposure to gasoline did not alter metronidazole pharmacokinetics. However, the effect of alcohol consumption on metronidazole CL requires further study. Drug interactions with warfarin, alcohol, disulfiram, phenytoin, lithium, phenobarbital, phenazone (antipyrine), prednisone, rifampicin, antacids and cholestyramine have been reported. No significant change in pharmacokinetics was observed with concurrent administration of theophylline, alprazolam, lorazepam, diazepam, ciprofloxacin or sulfasalazine. Studies conducted with cimetidine revealed varied findings. Metronidazole is generally well tolerated when administered in dosages of <2g per day. Some adverse reactions, such as gastrointestinal effects, neutropenia, neuropathies and certain central nervous system effects, appear to be related to the dosage and treatment duration. On the basis of the available data on metronidazole pharmacokinetics and microbiology, the traditional dosage recommendation of 500mg every 6h is more than adequate to treat most anaerobic infections. In fact, a regimen of 500mg every 8h can be expected to maintain serum concentrations above the minimum inhibitory concentrations of susceptible anaerobic organisms. Alternatively, once-daily administration has also been suggested. There is also some recent evidence to support a postantibiotic effect of metronidazole on certain anaerobic bacteria. The pharmacokinetics of other nitroimidazole derivatives are similar to those of metronidazole. They all have good oral absorption, and extensive hepatic metabolism and tissue distribution. The elimination half-lives of most of the derivatives are longer than that of metronidazole with the exception of nimorazole. Side effects of the derivatives are generally mild and they are usually well tolerated by patients. One notable exception is misonidazole; its use is often limited by frequent peripheral neuropathy.