Effect of Ciprofloxacin on Steady State Pharmacokinetics of Phenytoin in Rabbits

Indian Journal of Experimental Biology Vol. 37, January 1999, pp. 86-88

Effect of ciprofloxacin on steady state pharmacokinetics of phenytoin in rabbits

A F M S Islam, S K Garg* & V K Bhargava

Department of Pharmacology, Postgraduate Institute of Medical Education and Re ~ earch, Chandigarh - 160012, India

Received 5 March 1998; revised 13 October 1998

Present study was undertaken to detennine if an interaction exists during co-administration of cipro­ floxacin with phenytoin. Eight healthy male rabbits received oral phenytoin, 40 mg/kg, od, for 7 days. On day 7, phenytoin blood sampling was done at times 0,.0.1, 1, 2, 3, 4, 5, 6, 8 and 24 hr. From day 8 to 14 , phenytoin was co-administered with oral ciprofloxacin, 70 mg/kg, od. On day 14, blood samples were collected as previously described. Phannacokinetic analysis revealed significant decrease in steady

state maximum concentration (C max ) , through concentration (Cmin ), elimination half life (t 112 e) and the

area under plasma time concentration curve (AUCO_24 ) of phenytoin when co-administered with cipro­ floxacin. It warrants close monitoring of levels when these two agents are given simultaneously.

Ciprofloxacin, a fluoroquinolone antimicrobial Schroeder et a/. 6 reported modest increase by 24% agent is widely used in the treatment of community in serum DPH concentration co-administered with and hospital acq~ired infections due to susceptible ciprofloxacin in epileptic patients. Contrary to this organisms. Broad spectrum of antimicrobial activ­ initial study, a case report7 showed more than SO% ity and relatively infrequent and low level of mi­ decrease in serum DPH concentration resulting in crobial resistance against ciprofloxacin has made it break through seizure in an old epileptic patient an unique choice in infectious di seases. Addition­ while ' receiving a combination of DPH and ally it has favourable pharmacokinetic profile and ciprofloxacin. However, Job et af. 8 did not find attains l concentration equal to or two fold higher significant change in serum DPH concentration than the minimum inhibitory concentration in most during co-administration of ciprofloxacin in healthy ti ssues of the body. Ciprofloxacin impairs clear­ volunteers. 2 4 ance of theophylline , caffeine) and antipyrine , Hence the present study has been planned to suggesting inhibition of micro oomal cytochrome investigate the effect of ciprofloxacin on the steady P4S 0 by ciprofloxacin as the underlying mecha­ state pharmacokinetics of phenytoin in rabbits. ni sm of impaired clearance of these drugs. The study was carried out on 8 healthy male Phenytoin (DPH) is a commonly prescribed rabbits weighing between 1. Sand 2.S kg. The anti epileptic agent with low therapeutic index (8-20 animals were kept in isolation for 21 days prior to ug/ml) and undergoes extensive metabolism in the experimentation and standard _animal house hepatic endoplasmic reticulum by cytocbrome P4S0. conditions of 12 hour day-night cycle and the room It is cleared predominantly as parahydroxylated temperature of 2S 0 ± 2°C were maintained. The metabolite, S (p-hydroxyphenyl)-S-phenylhydantoin 5 rabbits were allowed to take water ad libitum and (p-HPPH) and its glucoronide conjugate . pellet diet (Him Agro Industries) once dai Iy at 1300 Because of narrow therapeutic range, drug hrs during experimentation days. interactions leading to an aiteration of plasma phenytoin concentration may be clinically Rabbits, after over night fast, received DPH important. Co-administration of ciprofloxacin (Sigma Chemical Company, USA) 40 mg/kg ad IIlcreases or decreases metabolism of DPH. orally through a soft orogastric tube for 7 days at 0800 hrs. On day 7, I ml each of blood samples *Corrcspondcn t author were coll ected in heparinized tubes at 0, O.S, 1, 2, 3, NOTES 87

4, 5, 6, 8 and 24 hr after drug administration from concentration (Cminss), elimination half life (t 1/2e) the marginal ear vein. Plasma was separated and and the area under the time plasma concentration stored at -20°C till assayed for DPH. From day 8, curve (AUC(}'24) of phenytoin are found to be the rabbits were treated with DPH 40 mg/kg, od significantly decreased when co-administered with along with ciprofloxacin (Alembic Chemicals ciproflox~cin as compared to those after DPH alone Works Co. Ltd., Vadodara) 70 mg/kg, ad orally at for 7 days. 0800 hrs for 7 days. On day 14, blood samples were 6 drawn at similar time intervals as described Schroeder et al. reported an increase in average previQusly. serum concentration of phenytoin from a baseline of Phenytoin assay was carried out using a reversed 11.3 mg/l to 14.4 mgIL on day 5 of concomitant phase high performance liquid chromatography therapy with ciprofloxacin in epileptic patients. The system (LDClMilton Roy, USA, Series 7800). An authors concluded that ciprofloxacin modestly ODS spherisorb column (25 cm x 4.6 mm ID) with elevates the phenytoin serum concentrations. a particle size of 5mu was used. The mobile phase However, the authors did not address pharmaco­ solvent, acetonitrile : methanol : water (18:36:46 kinetic parameters, such as Cmax, Tmax and AUe. In v/v/v) was delivered at flow rate of 1 mllmin at the present study, there was significant decrease in ambient temperature. Absorbance was monitored plasma phenytoin concentrations when co­ using a UV detector at 215nm at a sensitivity of 0.02 administered with ciprofloxacin. Similar reductions 9 aufs. Peak heights were used for quantitation • in plasma phenytoin concentrations was reported Steady state trough (Cminss) and peak plasma earlier by Dillard et aC in the case of a 74 year old phenytoin concentrations (Cmaxss) and time to reach who developed breakthrough. seizures while peak plasma concentration (Tmax> were calculated receiving phenytoin and ciprofloxacin due to from actual plasma data of 8 rabbits. The area under decrease in serum phenytoin concentration from the time-plasma concentration curve (AUC) was 14.7 and 6.3 mgIL. In a study on 4 human 8 claculated by trapeziodal rule, elimination half life volunteers, Job et al. did not find significant change (t1l2e) was calculated by least square regression in phenytoin steady state kinetics, although they analysis. reported marked reduction in both AUC and Cmax in Student's paired t test was applied to find out the one subject and a trend toward increased TOW( in level of significance. P<0.05 is taken as statistically three out of four subjects during concomitant significant. therapy of phenytoin and ciprofloxacin. Table 1 summarizes the results of the The mechanism by which ciprofloxacin decreases pharmacokinetic parameters of phenytoin steady plasma phenytoin concentrations is not known. state concentration after multiple doses of DPH and Results.of the present study point towards enhanced ciprofloxacin. The steady state maximum phenytoin metabloism by ciprofloxacin as there was concentration (Cmaxss), steady state through significant decrease in AUC, Cmax, Cmin and t 1I2e. Phenytoin is primarily metabolized by the hepatic Table I-Pharmacokinetic parameters of steady state phenytoin before and after multiple doses of ciprofloxacin. microsomal cytochrome P450 isozymes 2C9/10 [Values are mean ± SE from 8 animals] (ref. 5). Hence the possible mechanism is the induction of CYP2C91 10 by ciprofloxacin. A recent Parameters Phenytoin Phenytoin (14 day) report lO showed no significant difference in plasma (7 day) + ciprofloxacin concentrations in rabbits after 7 and 14 days (7 day) treatment of oral phenytoin at 60 mg/kg, od. Thus Cmin ( ~ g / ml ) 2. IO± 0. 11 0.81 ± 0.07· rules out the possibility of auto-induction as the Cmax (~g/ ml ) 18.96 ± 0.82 13.24 ± 0.74· cause of decrease in phenytoin concentration. T max (hr) 3.00 ± 0.00 3.00 ± 0.00 T 1/2 e (hr) 6.79 ± 0. 28 5.50 ± 0.19· One of us (AFMSI) was supported by a A UCO-14 (~g/ml.hr) 194.25 ± 10.75 99.65 ±_6 .24· Fellowship from World Health Organization. Authors are also thankful to Mr. K.J. Thomas for • P < 0.05 technical assistance. 88 INDIAN 1. EXP. BIOL., JANUARY 1999

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