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