PHRM 310- Toxicology: Assignment on history on toxicity of drug molecule.

Submitted to: Mahbubul Hoque Shihan Lecturer

Submitted by: Fariza Huq Oishi (ID: 2010-1-70-008) Sharmin Sheikh (ID: 2010-3-70-007) Debasree Paul (ID: 2010-3-70-036) Nabeela Zaman (ID: 2010-3-70-043) Samiya Khondaker Rinta (ID: 2010-3-70-048)

Department of Pharmacy East West University

5th May, 2013

Trovafloxacin (sold as Trovan by Pfizer) is a broad spectrum antibiotic. It was withdrawn from the market due to the risk of hepatotoxicity. It had better grampositive bacterial coverage and less gram-negative coverage than the previous fluoroquinolones. This new, third-generation fluoroquinolone with its dramatically increased activity against gram-positive and anaerobic bacteria--notably, Streptococcus pneumoniae and Bacteroides fragilis, have shown high rates of efficacy in pneumonia, bronchitis, and post-surgical intra-abdominal and gynaecological infections. History: Trovafloxacin was approved in 1998 and banned from pharmacies in 1999 after causing liver failure. In 1996, during a meningitis epidemic in Kano, Nigeria, the then-untested drug was administered to approximately 100 infected children. Eleven children died in the trial: five after taking Trovan and six after taking an older antibiotic used for comparison in the clinical trial. Others suffered blindness, deafness and brain damage. Trovafloxacin was banned in the EU in 1999 and in the U.S. was first restricted by the FDA to adult use. Since February 1998, 140 cases of serious liver damage have been reported among Trovan users. While most recovered after stopping the antibiotic, five patients died and three required liver transplants. Because of the risk of liver problems, these medicines are used only to treat serious bacterial infections, such as those that are life-threatening or when there is a risk of losing a limb. Mechanism of Action: Trovafloxacin inhibits bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. In the process of normal cell division and DNA replication/transcription, DNA must separate to expose the relevant portion of the strand (the portion to be copied). If this were to occur in stranded DNA, supercoiling or tension would be created within the helix. This is avoided by the action of an enzyme, DNA gyrase, which cuts the DNA allowing un-coiling for transcription/replication. The DNA gyrase then also acts to snip portions of the uncoiled DNA, where portions are re-inserted and rejoined, once again by DNA gyrase. The fluoroquinolones antibiotics inhibit the action of DNA gyrase. There is a similar enzyme in mammals, topoisomerase II, which is not inhibited by these drugs except at extremely high concentrations. Topoisomerase IV plays a key role in the

partitioning of the chromosomal DNA during bacterial cell division, however, the exact mechanism by which trovafloxacin inhibits this enzyme is not known. Adverse Effects: The most dangerous adverse effect related to trovafloxacin is hepatotoxicity. Others include: dizziness (2-11%); nausea (4-8%); headache (1-5%); lightheadedness (1-4%); pruritus (1-2%); abdominal pain (1%); diarrhea (1%); inflammation (1%); injection site reaction (1%); vaginitis (1%) The following effects are seen in <1%: Phototoxicity; Convulsions; Dyskinesia; Pseudomembranous colitis; Allergic/anaphylactoid reaction; Tendonitis; Bronchospasm; Interstitial nephritis; Anaphylaxis; Hepatic necrosis; Pancreatitis. Pregnancy & Lactation: Pregnancy Category is C. Drug is excreted in breast milk Pharmacology: Half-life elimination is 9-12 hrs. Protein binding is 76% and bioavailability is 88%. Time to peak, serum: oral: within 2 hr. Distribution: concentration in most tissues greater than plasma or serum. Metabolism: hepatic. Excretion: feces (43% as unchanged drug); urine (6% as unchanged drug). Usual Dosage: For adults: Community-acquired pneumonia: Oral, I.V.: 200 mg/day for 7-14 days. Complicated intra-abdominal infections, including postsurgical infections or gynecologic and pelvic infections: I.V.: 300 mg as a single dose followed by 200 mg/day orally for a total duration of 7-14 days. Skin and skin structure infections, complicated, including diabetic foot infections: Oral, I.V.: 200 mg/day for 10-14 days. Dosage adjustment in hepatic impairment: Mild to moderate cirrhosis: Initial dose for normal hepatic function: 300 mg I.V.; 200 mg I.V. or oral; 100 mg oral. Reduced dose: 200 mg I.V.; 100 mg I.V. or oral; 100 mg oral. Severe cirrhosis: No data available. Dosage Forms: Injection, as mesylate (alatrofloxacin): 5 mg/mL (40 mL, 60 mL). Tablet, as mesylate (trovafloxacin): 100 mg, 200 mg. Toxicology: Trovafloxacin contains a cyclopropylamine moiety which has a potential to be oxidized to reactive intermediate(s). P450s with heme-iron center and myeloperoxidase (MPO) generating hypochlorous acid (HClO) in the presence of

chloride ion are capable of bioactivating the cyclopropylamine moiety of trovafloxacin. It has been reported that trovafloxacin-induced hepatotoxicity may be mediated through the oxidation of the cyclopropylamine substructure to reactive intermediates that may form covalent adducts to hepatic proteins, resulting in damage to liver tissue.

Figure: Metabolites of trovafloxacin cause hepatotoxicity. Reference: Qin Sun, Ran Zhu, Frank W. Foss Jr. and Timothy L. Macdonald (2007) “Mechanisms of trovafloxacin hepatotoxicity: Studies of a model cyclopropylamine-containing system” Bioorganic & Medicinal Chemistry Letters. 17(24), pg.: 6682–6686. Goel K. (1999) “Elevated International Normalized Ratio associated with trovafloxacin.’’ Ann Intern Med. 131:72. Szarfman A, Chen M andBlum MD. (1995) “More on fluoroquinolone antibiotics and tendon rupture.’’ N Engl J Med. 332:193. (2013) “trovafloxacin” Available at: (Accessed: 5th May, 2013).

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