Itraconazole-ciprofloxacin interaction on the pharmacokinetics of the intestinal compartment: preliminary results in rats

Among their pharmacokinetic characteristics fluoroquinolones (FQs) ex-hibit transintestinal and biliary elimination; moreover, they may interferewith hepatic metabolism. Interactions of FQs with enzymeinhibitors orinducers could be possible during therapy. The inhibitory effects on thehepatic metabolism of Itraconanzole (Itz) should be considered in thekinetics of FQs.Objectives: To study the effect of Itz on intestinal kinetics ofCiprofloxacin (Cpx) following different administration schedule.Methods: Wistar rats (weight 174.0+12.5 g, mean+SD) divided inthree groups were treated as follows: group 1: Cpx, 15 mg/kg/day,orally administered by gavage for three days; group 2: Cpx two hoursafter oral administration of Itz (10 mg/kg/day) for three days; group3: Cpx for 3 days and Itz (10 mg/kg/day) on the 2nd and 3rd day ofCpx administration. Samples of blood, intestinal and hepatic tissuesand faeces were collected after three days of treatment, two hoursafter the last Cpx administration. Cpx concentrations were deter minedby microbiological assay (agar-well diffusion method, K. pneumoniae,Isosensistest agar).Results: reported in the table as mean+SDAfter three days of Itz administration the levels of Cpx increasedsignificantly in liver and faeces (not significantly) while decreased inserum (1/4 positive samples) and intestinal tissues. The administrationof Itz for 2 days in rats in treatment with Cpx induced a significantincrease of Cpx serum levels, a reduction of intestinal levels and amarked decrease in faeces in comparison to Cpx alone.Drugs Serum (mg/L) Intestinaltissue(mg/kg)Liver(mg/kg)Faeces(mg/kg)Cpx 0.05±0.01 (5/5) 10.4±12.2 0.0±0.0 231.6±279.9Cpx + Itz 3 days 0.06 (1/5) 4.2±2.7 1.0±0.3** 367.3±264.9Cpx + Itz 2nd-3rd d 0.2±0.2* (5/5) 7.2±2.4 0.0±0.0 111.8±29.7*p < 0.05, **p < 0.01 Students t test versus Cpx aloneConclusions: These preliminary results suggest a possible involvementof Itz on the intestinal secretory mechanisms of Cpx and changes inthe enterohepatic circulation. The inhibitory effects of Itz on the Cpxintestinal pharmacokinetics seems different according to timing of Itzadministration.MIUR PRIN 2003-Prot. N. 2003051858_003