Clinical Pharmacokinetics of Metronidazole and Other Nitroimidazole Anti-Infectives

Abstract

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.(ABSTRACT TRUNCATED AT 400 WORDS)

Treatment of Giardiasis

“…Nausea occurs in 5 to 15% of patients given standard multiday courses (135,151). In addition, pancreatitis, central nervous system toxicity at high doses (144,212), and transient, reversible neutropenia have been attributed to metronidazole (147). Patients should be warned to avoid alcohol while taking metronidazole.…”

Treatment of Infections Caused by Metronidazole-ResistantTrichomonas vaginalis

“…In contrast, nimorazole is rapidly absorbed and metabolized. It retains significant antiprotozoal activity, however, since its two major metabolites are much more active than the metabolites of metronidazole (65). More recently, the nitroimidazole EU11100 was developed in an attempt to obtain a drug with the trichomonicidal activity of metronidazole but without the side effects.…”

“…The one exception to this is misonidazole, which has consistently been shown to cause more serious side effects (peripheral neuropathy). Interest in misonidazole has therefore shifted away from a possible role in the treatment of trichomoniasis and is focusing on its radiosensitizing properties (65).…”

Colon Targeted Delivery Systems of Metronidazole Based on Osmotic Technology: Development and Evaluation

“…30) This is because the kinetics of osmotic drug release is directly related to solubility of drug within the core. Assuming a tablet core of pure drug, the fraction of drug released with zeroorder kinetics is given by; (2) where F(z) is the fraction released by zero-order kinetics, S the drug's solubility (g/cm 3 ), and r the density (g/cm 3 ) of the core tablet. Drugs with a solubility of Յ0.05 g/cm 3 would be released with Ն95% zero-order kinetics according to Eq.…”

“…3, due to the small osmotic pressure gradient. (3) Equation 3 describes drug release from osmotic pumps, where dm/dt is the drug delivery rate; A and h the membrane area and thickness, respectively; C is the concentration (or the solubility, when excess of drug is present in the core) of drug in the dispensed fluid, Dp is the osmotic pressure difference across the film, sL p is the hydraulic permeability of the membrane and p is the hydrostatic pressure within the core compartment. 31) According to Eq.…”