Effect of proguanil interaction on bioavailability of cloxacillin

To investigate a potential drug-drug interaction between proguanil (PG) and cloxacillin (Clox). Seven healthy adult volunteers received a single oral dose of Clox plus coadministration of single oral doses of PG and Clox in a simple cross-over manner after a wash-out period of 1 week. Total urine voided was collected at predetermined time intervals over 12 h. Amount of Clox in urine was determined by a reversed-phase high-pressure liquid chromatography method.

The mean maximum excretion rate [(dDu/dt)max] of Clox when taken alone was 16.13 +/- 2.92 mg/h at tmax of 1.86 +/- 01.07 hours, whereas in the presence of PG, it was 7.72 +/- 3.24 mg/h at tmax of 2.43 +/- 00.98 hours (P < 0.0001). The total amount of Clox excreted in urine (Du infinity) in 12 h was markedly reduced by coadministration with PG by up to 48% with Du infinity of 49.57 +/- 8.16 mg after Clox alone and 25.81 +/- 8.46 mg in the presence of PG (P < 0.0001). The tmax and t1/2-values obtained from the excretion rate plot were lengthened by 23 and 34%, respectively, in the presence of PG but the differences were not statistically significant (P > 0.05).

These pharmacokinetic values indicate slowed and diminished absorption (bioavailability) of Clox when concurrently administered with PG. The clinical implication is unknown. However, concomitant administration of the two drugs during antibacterial therapy should be done with caution so as to avoid subtherapeutic levels of Clox, which can lead to treatment failure and facilitate drug resistance.