FABAD J. Pharm. Sci., 29, 133-144, 2004 SCIENTIFIC REVIEWS Bioavailability File : Ornidazole Sinem Y. HIZARCIO⁄LU*, Zeynep AY*, Mine ÖZYAZICI*° Bioavailability File : Ornidazole Biyoyararlan›m Dosyas› : Ornidazole Summary Özet Ornidazole is a 5-nitroimidazole derivative drug which has anti- Ornidazol, antimikrobiyal etkisi olan 5-nitroimidazol türevi bir microbial action. It is used in the treatment of protozoal infecti- ilaçt›r. Protozoal enfeksiyonlar›n tedavisinde, ayr›ca anaerobik ons, and also in the treatment and prophylaxis of anaerobic bac- bakteriyel enfeksiyonlar›n tedavisi ve profilaksisinde kullan›l›r. terial infections. The mean ornidazole elimination half-life is 12 Ornidazolün ortalama eliminasyon yar› ömrü 12 saattir ve bu hours, significantly longer than that of some nitroimidazole deri- de¤er baz› nitroimidazol türevlerinin eliminasyon yar› ömründen vatives. This is a particular advantage for reducing the dosage frequency and duration of therapy in many of the relevant clini- daha uzundur. Bu özellik, dozaj s›kl›¤›n›n azalt›lmas› ve birçok cal infections. Ornidazole acts by damage of DNA strands or in- klinik enfeksiyonun tedavisinin süreklili¤i aç›s›ndan önemli bir hibition of their synthesis. It is widely distributed in body tissues avantajd›r. Ornidazol, DNA zincirinde hasar oluflturarak veya and fluids, including the cerebrospinal fluid. Ornidazole is meta- DNA sentezini inhibe ederek etki gösterir. Vücutta, serebrospinal bolized in the liver. It is excreted in the urine, mainly as conjuga- s›v› da dahil olmak üzere tüm s›v› ve dokularda genifl olarak da- tes and metabolites, and to a lesser extent in the feces and bile. ¤›l›r. Ornidazol karaci¤erde metabolize olur. At›l›m›, ço¤unlukla Ornidazole is administered orally, vaginally, or intravenously. In konjugatlar› ve metabolitleri halinde idrarla, daha az olarak ise this review, physicochemical, pharmacological and pharmacoki- feçes ve safrayla olur. Ornidazol oral, vajinal ve intravenöz yol- netic properties in addition to bioavailability of ornidazole are la verilebilir. Bu derlemede, ornidazolün fizikokimyasal, farma- discussed. kolojik ve farmakokinetik özellikleri ile birlikte biyoyararlan›m› Key Words : Ornidazole, bioavailability, pharmacokinetics, tart›fl›lm›flt›r. stability, physicochemical properties. Anahtar Kelimeler : Ornidazol, biyoyararlan›m, farmakoki- Received : 17.3.2005 netik, stabilite, fizikokimyasal özellikler. Revised : 3.6.2005 Accepted : 10.6.2005 INTRODUCTION Ornidazole is a 5-nitroimidazole derivative and is used in the treatment of susceptible protozoal infec- Nitroimidazole drugs have been used for over 20 ye- tions and also in anaerobic bacterial infections. It has ars, not only as major antimicrobial drugs but also as been used for amebic liver abscesses, duodenal ul- sensitizers of hypoxic tumors in conjunction with ra- cers, giardiasis, intestinal lambliasis and vaginitis3-5. diotherapy, thus possessing a wider spectrum of Ornidazole has recently been used with success in useful clinical activity than any other antibiotics1,2. patients with active Crohn’s disease6. It is more ef- * Ege University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 35100 Bornova, Izmir-TURKEY ° Corresponding author e-mail: [email protected] 133 H›zarc›o¤lu, Ay, Özyaz›c› fective against amebiasis than metronidazole, which Its pKa was detected as 2.4±0.14,5,11,16,17. is the most commonly used nitroimidazole derivati- ve in therapy7,8. Ornidazole has also been preferred The effect of gamma rays on ornidazole was investi- for surgical prophylaxis because of its longer elimi- gated and it was found that gamma irradiation of nation half-life and excellent penetration into lipidic ornidazole produces free radicals which are detec- tissues versus other nitroimidazole derivatives9,10. table by electron spin resonance (ESR) and appear relatively stable18. The plasma elimination half-life of ornidazole is 11 to 14 hours. Oral absorption of the drug is almost When the literature about stability of ornidazole is complete, with bioavailability of 90% and tmax ran- examined, it can be seen that ornidazole neither yields ging between 2 and 4 hours. Plasma protein binding the nucleus nor undergoes complete decomposition. is approximately 11 to 13%. It is metabolized to five It yields ornidazole diol and intermediate ornidazole metabolites. Two of the major active metabolites are epoxide in alkaline medium. The degradation kinetics M1 and M4, with M1 stemming from an oxidative of ornidazole have been found to be of the first order pathway and M4 via hydrolysis. Ornidazole and its both in solution and solid state (Fig. 2)19,20,21. metabolites are primarily excreted in the urine. Bet- ween 43 and 63% of the dose was recovered from urine, with <4% of the dose recovered as unchanged drug3,11-13. 19 Ornidazole is well tolerated, with the most common Figure 2. Reported degradation products of ornidazole. side effects being nausea, abdominal pain, vertigo, headache, diarrhea, flatulence, and skin rash14,15. The stability studies of ornidazole in alkaline condi- tions were done at a drug concentration of 1 mg/mL Physicochemical Properties in 0.1 M NaOH and the solution was heated at 80°C for 8 hours. The reaction in these conditions was so Ornidazole has a heterocyclic structure consisting of fast that the drug was degraded in a short time. For a nitroimidazole-based nucleus with a 2-hydroxy-3- oxidative conditions, initial studies were done at chloro-propyl group in position 1 and a methyl gro- drug strength of 1 mg/mL in 3% H2O2 and 30% up in position 2. It is synthesized from 5-nitroimida- H2O2. The drug was kept under the conditions of ro- zole derivatives. Ornidazole is known chemically as om temperature for a period of 24 hours. The drug 1-(2-hydroxy-3-chloropropyl)-2-methyl-5-nitroimida- was found to degrade in hydrogen peroxide. It was zole (C H ClN O). Its molecular weight is 219.63 (C 7 10 3 decomposed to an extent of 8% in 3% H2O2, and the 38.28%, H 4.59%, Cl 16.14%, N 19.13%, O 21.85%) and degradation increased to 53% in 30% H2O2. Reports the chemical formula can be seen in Figure 17,12,16. Or- also exist on the stability of the drug in 0.9% sodium nidazole is a white to yellowish microcrystalline chloride and PVC bags under different storage con- powder, with a melting point between 358-360 K. Its ditions22,23. 1% aqueous solution has a pH of approximately 6.6. Ornidazole is soluble in water, ether, ethanol and Identification and Quantification Methods chloroform (2.6, 2.4, over 50, over 50%, respectively). Polarographic, spectrophotometric, colorimetric, potentiometric, microbiologic, thin layer chroma- tographic, high-pressure liquid chromatographic (HPLC) and electrochemical methods have been described for determination of ornidazole in the do- 10,22,24-28 Figure 1. Structural formula of ornidazole. sage forms . Pulse polarography, gas chro- 134 FABAD J. Pharm. Sci., 29, 133-144, 2004 matography (GC) and HPLC procedures are repor- Bactericidal activity appears to be dependent on the ted for its analysis in biological fluids10,27,29. The me- formation of a redox intermediate metabolite in the asurement of ornidazole in biological fluids allows bacterium. This toxic metabolite may interact prima- the dosage to be adjusted in patients suffering from rily with DNA, RNA or intracellular proteins; howe- malabsorption or pathological conditions which ver, its main effects are DNA strand breakage, inhi- modify excretion of the drug. bited repair and ultimately disrupted transcription and cell death3,31-35. Spectrophotometric determination of ornidazole is a simple method and is based on the reduction of a Owing to its similar chemical properties, ornidazole nitro group to a primary amino group which is then shares the same mechanism of action and spectrum reacted with p-dimethylaminobenzaldehyde (p-DA- of microbiological activity as other nitroimidazole BA) to give a red-colored product. During spectrop- agents against anaerobes and protozoa3,31,36-38. The- hotometric studies, a linear correlation was obtained refore, it is a drug of choice for treatment of a large between absorbance and ornidazole concentrations variety of diseases, including intra-abdominal, pul- over the range of 0.75-5 µg/mL24. The GC method monary and brain abscesses, chronic sinusitis and for blood involves a derivatization step, and the me- otitis, and genital tract infections10,32,39. tabolites are not determined30. HPLC method is ra- pid, selective and reproducible, by using an internal Uses and Administrations standard. Furthermore, the method allows metabo- lites to be separated and measured. In HPLC studi- Ornidazole is given by mouth in tablets after food, es, the limits of quantifications were: 0.5µg/mL or intravenously. When given intravenously, soluti- (plasma, cerebrospinal fluid) and 0.6µg/mL (urine) ons of ornidazole should be diluted to 5 mg or less for ornidazole; and 0.05µg/mL (plasma, cerebrospi- per mL and 100 or 200 mL infused over 15 to 30 mi- 12 nal fluid) and 0.3µg/mL (urine) for both M4 and nutes. It has also been given by vaginal pessary . M110,26. Electrochemical method for the determinati- on of ornidazole has the advantage of being rapid, In amebiasis, 500 mg of ornidazole is given twice da- simple and inexpensive28. ily by mouth for 5 to 10 days. Patients with amebic dysentery may be given 1.5 g as a single daily dose Pharmacology for 3 days. In severe amebic dysentery and amebic liver abscess, ornidazole may be given by intraveno- Mechanism of action us infusion in a dose of 0.5 to 1 g initially, followed by 500 mg every 12 hours for 3 to 6 days12,40,41. 5-Nitroimidazoles belong to the nitroheterocyclic fa- mily of compounds widely used for the treatment or In giardiasis, 1 or 1.5 g of drug is given by mouth as 12,42-44 prophylaxis of infections due to anaerobic bacteria a single daily dose for 1 or 2 days .