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Fluoroquinolone Drug Interactions: Ciprofloxacin and Levofloxacin

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Presentation on theme: "Fluoroquinolone Drug Interactions: Ciprofloxacin and Levofloxacin"— Presentation transcript:

1 Fluoroquinolone Drug Interactions: Ciprofloxacin and Levofloxacin
Nicholas Au Pharm.D. Candidate 2009

2 Fluoroquinolone Class
Excellent safety and tolerability Popular alternative to penicillin allergic patients Ciprofloxacin and Levofloxacin were listed in the top 200 drugs by sales in 2007

3 Mechanism of Action Inhibit topoisomerase II (DNA Gyrase) and IV, an enzyme needed in bacterial DNA replication Bactericidal, concentration-dependent killing Blondeau JM Surv Ophthalmol. 2004

4 Ciprofloxacin 2nd generation: good gram (-) coverage
Infections of the urinary tract, bone and joint, skin, sinus, etc. Substrate of: SLC22A8, SLCO1A2, ABCG2, UGT1A1, ABCC1, ABCB1 (P-gp) Inhibitor of: CYP1A2, CYP3A4, SLC22A8

5 Levofloxacin 3nd generation: Both gram (-) and gram (+) coverage as well as atypical pathogens Very similar indications to ciprofloxacin, but also covers community acquired pneumonia Substrate of: SLCO1A2, SLC22A2, ABCB1 Inhibitor of: SLC22A2, SLC22A4

6 Drug interactions on GenMedRX
Ciprofloxacin listed 36 different drug interactions Levofloxacin listed 11 drug interactions 12 new interactions were added to the GenMedRx database with these drugs found from PubMed, Stockley’s, and BNF Ciprofloxacin: levothyroxine, duloxetine, zolmitriptan Levofloxacin: cimetidine, lithium, amiodarone Fluoroquinolones: antidiabetics, NSAIDs, probenecid, magnesium containing drugs, sucrafate, didanosine

7 Ciprofloxacin as the perpetrator drug
Mechanism Drug CYP1A2 inhibition caffeine, clozapine, mexiletine, olanzapine, R-warfarin, rasagiline, ropinirole, ropivacaine, theophylline, tizanidine, duloxetine, zolmitriptan CYP3A4 inhibition cyclophosphamide, sildenafil, glyburide, cyclosporine Inhibition of organic ion transporters methotrexate, probenecid, procainamide, cimetidine Reduced enterohepatic recycling Ethinyl estradiol Lack of interaction Diazepam, ethanol Unknown isoniazid

8 Ciprofloxacin as the victim drug
Mechanism Drug Induction of ABCB1 (P-gp) Doxorubicin, rifampin Inhibition of organic ion transporters Probenecid Unknown Methadone, morphine, omeprazole, foscarnet

9 Levofloxacin as the perpetrator drug
Mechanism Drug Inhibition of organic ion transporters cimetidine, procainamide Lack of interaction digoxin, oxycodone, theophylline, AZT Unknown Cyclosporine, tacrolimus

10 Levofloxacin as the victim drug
Mechanism Drug Inhibition of organic ion transporters cimetidine A clinical study showed that cimetidine decreased the renal clearance and increased the half-life of levofloxacin in the body.  However, the interaction was not clinically significant and does not warrant a dose adjustment of levofloxacin Fish DN, Chow AT. Clin Pharmacokient

11 Common interactions with both drugs
Mechanism Drug Complexation of drug to fluoroquinolone antacids, iron salts, calcium salts, magnesium salts, zinc oxide, didanosine Disruption of normal gut flora warfarin Unknown Antidiabetics, NSAIDs, probenecid

12 GenMedRX Algorithm Online program that predicts the outcomes of the drug-drug interaction even when clinical data is lacking Computes a score that determines % change in AUC of the victim drug when accounting for factors such as metabolic pathways, inhibitor strength (Ki), level of induction, and the strength of evidence in the literature (if any) Point Score Change Reported (AUC) More than -100 % -50 to -100 -60-90% -25 to -50 -25-60% 0 to -24 0 to -25% 0 to +24 0 to +25% +25 to +50 +25-75% +50 to +100 75-150% More than 100 Over 150%

13 Examples of Algorithm Results
Victim / Culprit Substr. of Inhibitor Ki (Points) Inducer (Points) Path Size Change Points clozapine / ciprofloxacin CYP1A2 2 (50) 0.25 12.5 CYP3A4 3 (50) cyclophosphamide / ciprofloxacin 0.2 10 Cipro / probenecid Glucuronidation 0.38 19 theophylline / levofloxacin digoxin / levofloxacin 0.08 4 Many drugs involved in an interaction with ciprofloxacin or levofloxacin were not fully calculated by the algorithm because the metabolic pathways involved were minor, but still generally predicted the AUC change in the correct direction (increase or decrease)

14 Acknowledgements Thanks to:
Jessica Oesterheld for her guidance through GenMedRx Kristine Ashcraft and Don Rule for answering questions when needed Bob Patterson in fixing the editor program Howard Coleman for establishing this clerkship

15 Questions?

16 References Pharmacy Times. Top 200 prescription drugs of May Accessed 28 January _003.asp Fish DN, Chow AT. The clinical pharmacokinetics of levofloxacin. Clin Pharmacokient. 1997;32(2):101-19 Andriole VT. The quinolones: past, present, and future. Clin Infect Dis ;15;41 Suppl 2:S113-9. Alvarez AI, Pérez M, Prieto JG, Molina AJ, Real R, Merino G. Fluoroquinolone efflux mediated by ABC transporters. J Pharm Sci. 2008;97(9): Blondeau JM. Fluoroquinolones: mechanism of action, classification, and development of resistance. Surv Ophthalmol. 2004;49 Suppl 2:S73-8. Wikipedia. Ciprofloxacin January < Wikipedia. Levofloxacin January <

17 References Cont. British National Formulary. Ciprofloxacin Interactions January < British National Formulary. Levofloxacin Interactions January < FDA. Ciprofloxacin January < s26,21473s24lbl.pdf FDA. Levofloxacin January < s26,21473s24lbl.pdf

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