Significant Pharmacokinetic Interactions Between Quinine and Ampicillin-Cloxacillin Combination.

INTRODUCTION: The co-existence of malaria with bacterial infections is common in the tropics, hence the concurrent use of antimalarials and antibiotics. OBJECTIVE: This study aimed to investigate the effect on pharmacokinetics and antimicrobial activity of co-administration of quinine and combined ampicillin-cloxacillin. METHODS: In total, 14 healthy adults received single oral doses of ampicillin-cloxacillin combination alone and with quinine in a randomized crossover manner. Urine samples collected at predetermined intervals over 48 h were analysed. The effect of quinine on minimum inhibitory concentrations (MICs) of ampicillin and cloxacillin were determined against Staphylococcus aureus by agar diffusion, agar dilution, and broth dilution. RESULTS: Quinine significantly reduced the rate and extent of excretion of ampicillin and cloxacillin (p < 0.0002). The total amounts of ampicillin and cloxacillin excreted unchanged (Du(∞)) alone were 217.10 ± 53.82 and 199.0 ± 64.29 mg versus 126.40 ± 50.63 and 135.20 ± 52.24 mg, respectively, with quinine. Respective maximum excretion rates (dDu/dt max) for ampicillin and cloxacillin were 43.55 ± 19.41 and 77.64 ± 29.65 mg/h alone versus 18.01 ± 8.52 and 53.16 ± 20.72 mg/h with quinine. This indicates a significant reduction in Du(∞)and dDu/dt max by 41.78 and 58.65 % for ampicillin and 32.06 and 31.53 % for cloxacillin. Conversely, the disposition of quinine was unaffected by ampicillin-cloxacillin (p > 0.1). The MIC of antibiotics alone versus with quinine, respectively, were 0.11 ± 0.04 and 0.78 ± 0.1 µg/ml for ampicillin, and 0.18 ± 0.1 and 0.92 ± 0.4 µg/ml for cloxacillin, with a five- to sevenfold increase (p > 0.01); indicating a decrease in antimicrobial activity by quinine. CONCLUSIONS: Quinine therefore, reduced the bioavailability and the antimicrobial activity of ampicillin-cloxacillin upon co-administration, which may have therapeutic implications. Caution is required with the co-administration of these medicines.

Effect of multidrug resistance gene-1 (ABCB1) polymorphisms on the single-dose pharmacokinetics of cloxacillin in healthy adult Chinese men.

BACKGROUND: Plasma concentrations of cloxacillin have been found to vary as much as 20-fold among individuals receiving the same oral dose. There is evidence that cloxacillin may be a substrate for P-glycoprotein, suggesting that polymorphisms in the ABCB1 gene may be a contributing factor to the observed variability in plasma cloxacillin concentrations. OBJECTIVE: This study investigated the effect of ABCB1 polymorphisms on the pharmacokinetic profile of cloxacillin in healthy subjects. METHODS: A single oral dose of cloxacillin 500 mg was administered to healthy Chinese male subjects under fasting conditions. Serial blood and urine samples were collected for up to 6 hours after administration. A high-performance liquid chromatography method was used to determine plasma cloxacillin pharmacokinetics and urinary excretion. A polymerase chain reaction technique was used for genotyping of 3 single nucleotide polymorphisms (SNPs) of the ABCB1 gene: exon 12 C1236T, exon 21 G2677T/A, and exon 26 C3435T. Cloxacillin pharmacokinetic parameters and urinary excretion were then compared according to genotype and haplotype groups. RESULTS: The study included 18 healthy Chinese male subjects who ranged in age from 21 to 26 years, had a mean weight ranging from 55.6 to 70.6 kg, and had normal renal function at baseline (mean [SD] serum creatinine, 93.4 [11.0] micromol/L). Plasma concentrations of cloxacillin were generally lower in the group carrying the 1236CC genotype (n = 3) compared with those carrying the 1236CT genotype (n = 9) or the 1236TT genotype (n = 6). Compared with the other groups, carriers of the 1236CC genotype had a significantly lower mean Cmax (-53%; P = 0.013) and AUC(0-infinity) (-40%; P = 0.044), and a significantly higher mean apparent oral clearance (35%; P = 0.013). They also had significantly lower urinary excretion of cloxacillin over 6 hours (-52%; P = 0.027). There were no significant differences in cloxacillin t(1/2) or renal clearance between the 3 C1236T genotypes, nor was the G2677T or C3435T SNP associated with any significant changes in the cloxacillin pharmacokinetic profile. Among subjects with 1 of the 3 major haplotype pairs, those carrying the CGC/CGC pair had a significantly lower C(max) (P = 0.017), AUC (P = 0.032), and urinary excretion of cloxacillin (P = 0.026) compared with those carrying the CGC/TGC and TTT/TTT pairs. CONCLUSIONS: In this small population of healthy Chinese men, the C1236T variant of ABCB1 appeared to be an important contributor to interindi-vidual differences in plasma cloxacillin exposure, most likely through an effect on oral absorption rather than on disposition. Studies of multiple doses in larger sample sizes are needed to confirm these findings.

On-line clean-up and screening of oxacillin and cloxacillin in human urine and plasma with a weak ion exchange monolithic column.

A weak ion exchange monolithic column prepared by modifying the GMA-MAA-EDMA (glycidyl methacrylate-methacrylic acid-ethylene glycol dimethacrylate) monoliths with ethylenediamine was applied to remove matrix compounds in biological fluid. Using this monolithic column, on-line clean-up and screening of oxacillin and cloxacillin in human urine and plasma samples had been investigated. Chromatography was performed by reversed-phase HPLC on a C(18) column with ultraviolet detection at 225 nm. Results showed that the ion exchange monolithic column could be used for deproteinization and retaining oxacillin and cloxacillin in human urine and plasma, which provided a simple and fast method for assaying drugs in human urine and plasma.

HPLC determination of ciprofloxacin, cloxacillin, and ibuprofen drugs in human urine samples.

This paper reports, for the first time, a liquid chromatographic method for the simultaneous determination of three frequently co-administered active principles, two antibiotics, ciprofloxacin (CIPRO) and cloxacillin (CLOXA) belonging to the fluoroquinolones and beta-lactam families, respectively, and ibuprofen (IBU), a non-steroidal anti-inflammatory drug. The chromatographic separation was performed on a C-18 analytical column, using isocratic elution with methanol-acetonitrile-pH 3 formate buffer (CT = 0.1 M) (15:12:73, v/v/v) for 3 min and, after that, a linear gradient with methanol-acetonitrile (88:12, v/v) for 8 min. Several absorption spectra were obtained for each peak using a DAD detector. Chromatograms at the maximum absorption wavelength for each analyte, 220 nm for both IBU and CLOXA, and 280 nm for CIPRO were selected as the most suitable. The proposed chromatographic method requires about 15 min per sample. The presence of a urine background was tested and no interference was found. The method was satisfactorily applied to the determination of CIPRO, CLOXA, and IBU, in fortified urine, and in urine samples from a patient undergoing treatment with these three active principles, among others. Limits of quantification in urine were 1.00, 1.70, and 2.87 microg/mL for CIPRO, CLOXA, and IBU, respectively.

Effect of proguanil interaction on bioavailability of cloxacillin.

METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Simultaneous high-pressure liquid chromatographic analysis of ampicillin and cloxacillin in serum and urine.

A rapid, specific and sensitive high pressure liquid chromatographic (HPLC) assay for the simultaneous determination of ampicillin and cloxacillin in serum and urine is developed. Ampicillin, cloxacillin and cephalexin (internal standard) were eluted from a 6.5 mu Synchropack RPP reversed phase column at ambient temperature using a mobile phase comprised of methanol:water (3/7v/v) and containing 0.011 M sodium-n-octane sulphonate, 0.005 M NaH2PO4 and 1.3% v/v of 0.5 M HCl (pH 2.7). The analysis time required no longer than 11 min. Equations are presented for the linear relationships between the peak height ratios of ampicillin/cephalexin and cloxacillin/cephalexin over the range 10-80 micrograms/ml (ampicillin) and 5-25 micrograms/ml (cloxacillin), respectively. The sensitivity limits for ampicillin and cloxacillin in serum and urine were 5 micrograms/ml and 1 microgram/ml, respectively. Quality criteria such as accuracy, precision and specificity were studied extensively. We investigated the applicability of the HPLC assay for the developed simultaneous determination of the cumulative amounts of ampicillin and cloxacillin, excreted unchanged in urine after an oral dose containing 500 mg ampicillin and 500 mg cloxacillin to a human volunteer.

Analysis of isoxazolyl penicillins and their metabolites in body fluids by high-performance liquid chromatography.

A high-performance liquid chromatographic assay method to quantitate the isoxazolyl penicillins, their active metabolites, and their penicilloic acids in serum or urine is described. Separation and analysis is performed using reversed-phase chromatography. Urine samples, after the appropriate dilution, can be assayed directly. Serum samples (0.1 ml) are either extracted with methylene chloride or treated with perchloric acid--methanol. Serum levels as low as 0.4 microgram/ml (extraction procedure) can be assayed accurately.