Clarithromycin laurate salt: physicochemical properties and pharmacokinetics after oral administration in humans.

OBJECTIVE: To prepare and characterize the physicochemical and pharmacokinetic properties of clarithromycin laurate (CLM-L), a fatty acid salt of clarithromycin (CLM). METHODS: CLM-L was prepared by a simple co-melting process. The formation of CLM-L was confirmed using FTIR, 1H NMR, and 13C NMR. Solubility, intrinsic dissolution rate (IDR), and partitioning properties of CLM-L were determined and compared to those of CLM. Bioavailability of CLM from CLM-L tablets was evaluated in healthy volunteers and compared to immediate release CLM tablets. RESULTS: CLM-L showed lower aqueous solubility, higher partitioning coefficient, and slower dissolution rate. Tablets of CLM-L also showed a significantly slower in vitro release in comparison to CLM tablets. Cmax, Tmax and AUC0→∞ of CLM-L tablets and immediate release CLM tablets did not show a significant difference. However, the AUC0→∞ for the CLM-L tablets tended to be higher than that of CLM tablets at all-time points. CONCLUSION: CLM-L was successfully prepared and its formation was confirmed. CLM-L was more hydrophobic than CLM. It exhibited a slight in vivo absorption enhancement in comparison to CLM. However, its pharmacokinetic behavior was comparable to that of CLM.

Assessment of inter-racial variability in CYP3A4 activity and inducibility among healthy adult males of Caucasian and South Asian ancestries.

PURPOSE: Cytochrome P450 (CYP) 3A4 is responsible for the metabolism of more than 30% of clinically used drugs. Inherent between subject variability in clearance of CYP3A4 substrates is substantial; by way of example, midazolam clearance varies by > 10-fold between individuals before considering the impact of extrinsic factors. Relatively little is known about inter-racial variability in the activity of this enzyme. METHODS: This study assessed inter-racial variability in midazolam exposure in a cohort (n = 30) of CYP3A genotyped, age-matched healthy males of Caucasian and South Asian ancestries. Midazolam exposure was assessed at baseline, following 7 days of rifampicin and following 3 days of clarithromycin. RESULTS: The geometric mean baseline midazolam area under the plasma concentration curve (AUC0-6) in Caucasians (1057 µg/L/min) was 27% greater than South Asians (768 µg/L/min). Similarly, the post-induction midazolam AUC0-6 in Caucasians (308 µg/L/min) was 50% greater than South Asians (154 µg/L/min), while the post-inhibition midazolam AUC0-6 in Caucasians (1834 µg/L/min) was 41% greater than South Asians (1079 µg/L/min). The difference in baseline AUC0-6 between Caucasians and South Asians was statistically significant (p ≤ 0.05), and a trend toward significance (p = 0.067) was observed for the post-induction AUC0-6 ratio, in both unadjusted and genotype adjusted analyses. CONCLUSIONS: Significantly higher midazolam clearance was observed in healthy age-matched males of South Asian compared to Caucasian ancestry that was not explained by differences in the frequency of CYP3A genotypes.

Pharmacokinetic drug interaction and safety after coadministration of clarithromycin, amoxicillin, and ilaprazole: a randomised, open-label, one-way crossover, two parallel sequences study.

PURPOSE: Ilaprazole, the latest proton pump inhibitor, can be used with clarithromycin and amoxicillin as a triple therapy regimen for eradicating Helicobacter pylori. The aim of this study was to evaluate pharmacokinetic drug interactions and safety profiles after coadministration of clarithromycin, amoxicillin, and ilaprazole. METHODS: A randomised, open-label, one-way crossover, two parallel sequences study was conducted in 32 healthy subjects. In part 1, the subjects received a single dose of ilaprazole 10 mg in period 1 and clarithromycin 500 mg and amoxicillin 1000 mg twice daily for 6 days in period 2. In part 2, the subjects received clarithromycin 500 mg and amoxicillin 1000 mg once in period 1 and ilaprazole 10 mg twice daily for 6 days in period 2. In both sequences, the three drugs were coadministrated once on day 5 in period 2. Pharmacokinetic evaluations of ilaprazole (part 1), and clarithromycin and amoxicillin (part 2) were conducted. RESULTS: Twenty-eight subjects completed the study. For ilaprazole, the peak concentration (Cmax) slightly decreased from 479 (ilaprazole alone) to 446 ng/mL (triple therapy) [Geometric least square mean ratio (90% confidence interval), 0.93 (0.70-1.22)]. The area under the concentration-time curve from 0 h to the last measurable concentration (AUClast) slightly increased from 3301 to 3538 µg·h/mL [1.07 (0.85-1.35)]. For clarithromycin, the Cmax slightly decreased from 1.87 to 1.72 µg/mL [0.90 (0.70-1.15)], and AUClast slightly increased from 14.6 to 16.5 µg·h/mL [1.09 (0.87-1.37)]. For amoxicillin, the Cmax slightly decreased from 9.37 to 8.14 µg/mL [0.86 (0.74-1.01)], and AUClast slightly decreased from 27.9 to 26.7 µg·h/mL [0.98 (0.83-1.16)]. These changes in the PK parameters of each drug were not statistically significant. CONCLUSIONS: The coadministration of ilaprazole, clarithromycin, and amoxicillin was tolerable and did not cause a significant PK drug interaction. Thus, a triple therapy regimen comprising ilaprazole, clarithromycin, and amoxicillin may be an option for the eradication of H. pylori. Clinicaltrials.gov number: NCT02998437.

Assessment of potential interaction between simvastatin and clarithromycin in healthy adult male subjects.

Cardiac patients with weak immune system are susceptible to bacterial infections. Their prescriptions frequently contain simvastatin and clarithromycin together. The objective of present project was to assess the potential interaction between simvastatin and clarithromycin by evaluating the clarithromycin effects on the pharmacokinetics of simvastatin in healthy adult male subjects. The study design comprised of two phases, used at interval of one week. In first phase simvastatin 20 mg alone was administered to each volunteer. In second phase, co-administration of simvastatin 20 mg with clarithromycin 250 mg was made under similar specified conditions. Blood samples were collected at specified time intervals. Simvastatin plasma concentrations were analyzed through High Performance Liquid Chromatography with UV detector at 238 nm wavelength. Using one compartment open model, MW/PHARM version 3.02 software program was used by F. Rombut for pharmacokinetic parameters calculation. Clarithromycin co-treatment resulted in 2.3 fold increase in maximum plasma concentration Cmax (from 2.47±0.34 ng.mL-1 to 5.66±1.18 ng.mL-1; p<0.05) and 3.9 fold increase in area under time versus concentration curve from 0 to 10 hours AUC0-10 (from 15.10±3.73 ng.hr.mL-1 to 58.49±15.73 ng.hr.mL-1; p<0.05) of simvastatin. These results suggest that co-prescription of simvastatin and clarithromycin should be avoided to minimize the adverse events resulting from high simvastatin concentration, without sacrificing therapeutic worth of simvastatin.

Involvement of intestinal permeability in the oral absorption of clarithromycin and telithromycin.

The involvement of intestinal permeability in the oral absorption of clarithromycin (CAM), a macrolide antibiotic, and telithromycin (TEL), a ketolide antibiotic, in the presence of efflux transporters was examined. In order independently to examine the intestinal and hepatic availability, CAM and TEL (10 mg/kg) were administered orally, intraportally and intravenously to rats. The intestinal and hepatic availability was calculated from the area under the plasma concentration-time curve (AUC) after administration of CAM and TEL via different routes. The intestinal availabilities of CAM and TEL were lower than their hepatic availabilities. The intestinal availability after oral administration of CAM and TEL increased by 1.3- and 1.6-fold, respectively, after concomitant oral administration of verapamil as a P-glycoprotein (P-gp) inhibitor. Further, an in vitro transport experiment was performed using Caco-2 cell monolayers as a model of intestinal epithelial cells. The apical-to-basolateral transport of CAM and TEL through the Caco-2 cell monolayers was lower than their basolateral-to-apical transport. Verapamil and bromosulfophthalein as a multidrug resistance-associated proteins (MRPs) inhibitor significantly increased the apical-to-basolateral transport of CAM and TEL. Thus, the results suggest that oral absorption of CAM and TEL is dependent on intestinal permeability that may be limited by P-gp and MRPs on the intestinal epithelial cells.

Clinical validation of the analysis of linezolid and clarithromycin in oral fluid of patients with multidrug-resistant tuberculosis.

Linezolid plays an increasingly important role in the treatment of multidrug-resistant tuberculosis (MDR-TB). However, patients should be carefully monitored due to time- and dose-dependent toxicity. Clarithromycin plays a more modest role. Therapeutic drug monitoring may contribute to assessment of treatment regimens, helping to reduce toxicity while maintaining adequate drug exposure. Oral fluid sampling could provide a welcome alternative in cases where conventional plasma sampling is not possible or desirable. The aim of this study was to clinically validate the analysis of linezolid and clarithromycin and its metabolite hydroxyclarithromycin in oral fluid of patients with multidrug-resistant tuberculosis. Serum and oral fluid samples were simultaneously obtained and analyzed by using validated methods, after extensive cross-validation between the two matrices. Passing-Bablok regressions and Bland-Altman analysis showed that oral fluid analysis of linezolid and clarithromycin appeared to be suitable for therapeutic drug monitoring in MDR-TB patients. No correction factor is needed for the interpretation of linezolid oral fluid concentrations with a ratio of the linezolid concentration in serum to that in oral fluid of 0.97 (95% confidence interval [CI], 0.92 to 1.02). However, the clarithromycin concentration serum/clarithromycin concentration in oral fluid ratio is 3.07 (95% CI, 2.45 to 3.69). Analysis of hydroxyclarithromycin in oral fluid was not possible in this study due to a nonlinear relationship between the concentration in serum and that in oral fluid. In conclusion, the analysis of linezolid (no correction factor) and clarithromycin (correction factor of 3) in oral fluid is applicable for therapeutic drug monitoring in cases of multidrug-resistant tuberculosis as an alternative to conventional serum sampling. Easy sampling using a noninvasive technique may facilitate therapeutic drug monitoring for specific patient categories.

Interaction of ambrisentan with clarithromycin and its modulation by polymorphic SLCO1B1.

PURPOSE: We assessed the effect of cytochrome P450 (CYP) 3A4 and the OATP1B1 inhibitor clarithromycin on ambrisentan steady-state kinetics and its relationship to the SLCO1B1 15 haplotype in healthy volunteers. METHODS: In this open-label, monocenter, one-sequence crossover clinical trial ten male healthy participants were stratified according to CYP2C19 and SLCO1B1 (encoding for OATP1B1) genotype into two groups: group 1 (n = 6), with CYP2C19 1/1 (extensive metabolizer, EM) and SLCO1B1 wild-type; group 2 (n = 4), with CYP2C19 EM and homozygous (n = 3) or heterozygous for SLCO1B1 15 (n = 1). The participants were administered a once-daily oral dose of 5 mg ambrisentan on study days 1 and days 3-14 and twice-daily oral doses of 500 mg clarithromycin on study days 11-14. To monitor CYP3A activity 3 mg midazolam was given orally 1 day before the first ambrisentan administration and on days 1, 10, and 14 of ambrisentan treatment. Ambrisentan plasma kinetics was assessed on days 1 (single dose), 10 (steady-state), and 14 (CYP3A4/OATP1B1 inhibition by clarithromycin). RESULTS: Consistent with the expectation that ambrisentan does not induce its own metabolism, ambrisentan exposure and peak concentration (Cmax) were similar after the first dose and at steady-state. Clarithromycin increased the area under the plasma concentration-time curve of ambrisentan by 41 % and Cmax by 27 % (n = 10, both p < 0.05). No contribution of SLCO1B1*15 to the extent of this interaction was observed. CONCLUSIONS: Clarithromycin increased ambrisentan exposure to a similar extent to ketoconazole, namely, clinically minor and likely irrelevant.

Urinary metabolic markers reflect on hepatic, not intestinal, CYP3A activity in healthy subjects.

Intestinal cytochrome P450 3A (CYP3A) plays an important role in oral drug metabolism, but only endogenous metabolic markers for measuring hepatic CYP3A activity were identified. Our study evaluated whether hepatic CYP3A markers reflected intestinal CYP3A activity. An open-label, three-period, six-treatment, one-sequence clinical trial was performed in 16 healthy Korean males. In the control phase, all subjects received a single dose of intravenous (IV) and oral midazolam (1 mg and 5 mg, respectively). Clarithromycin (500 mg) was administered twice daily for 4 days to inhibit hepatic and intestinal CYP3A, and 500 mL of grapefruit juice was given to inhibit intestinal CYP3A. Clarithromycin significantly inhibited total CYP3A activity, and the clearance of IV and apparent clearance of oral midazolam decreased by 0.15- and 0.32-fold, respectively. Grapefruit juice only reduced the apparent clearance of oral midazolam by 0.84-fold, which indicates a slight inhibition of intestinal CYP3A activity. Urinary markers, including 6ß-OH-cortisol/cortisol and 6ß-OH-cortisone/cortisone, were significantly decreased 0.5-fold after clarithromycin administration but not after grapefruit juice. The fold changes in 6ß-OH-cortisol/cortisol and 6ß-OH-cortisone/cortisone did not correlate to changes in intestinal availability but did correlate to hepatic availability. In conclusion, endogenous metabolic markers are only useful to measure hepatic, but not intestinal, CYP3A activity.

Pharmacokinetics of rifampin and clarithromycin in patients treated for Mycobacterium ulcerans infection.

In a randomized controlled trial in Ghana, treatment of Mycobacterium ulcerans infection with streptomycin (SM)-rifampin (RIF) for 8 weeks was compared with treatment with SM-RIF for 4 weeks followed by treatment with RIF-clarithromycin (CLA) for 4 weeks. The extent of the interaction of RIF and CLA combined on the pharmacokinetics of the two compounds is unknown in this population and was therefore studied in a subset of patients. Patients received CLA at a dose of 7.5 mg/kg of body weight once daily, rounded to the nearest 125 mg. RIF was administered at a dose of 10 mg/kg, rounded to the nearest 150 mg. SM was given at a dose of 15 mg/kg once daily as an intramuscular injection. Plasma samples were drawn at steady state and analyzed by liquid chromatography-tandem mass spectroscopy. Pharmacokinetic parameters were calculated with the MW/Pharm (version 3.60) program. Comedication with CLA resulted in a 60% statistically nonsignificant increase in the area under the plasma concentration-time curve (AUC) for RIF of 25.8 mg x h/liter (interquartile ratio [IQR], 21.7 to 31.5 mg x h/liter), whereas the AUC of RIF was 15.2 mg x h/liter (IQR, 15.0 to 17.5 mg x h/liter) in patients comedicated with SM (P = 0.09). The median AUCs of CLA and 14-hydroxyclarithromycin (14OH-CLA) were 2.9 mg x h/liter (IQR, 1.5 to 3.8 mg x h/liter) and 8.0 mg x h/liter (IQR, 6.7 to 8.6 mg x h/liter), respectively. The median concentration of CLA was above the MIC of M. ulcerans, but that of 14OH-CLA was not. In further clinical studies, a dose of CLA of 7.5 mg/kg twice daily should be used (or with an extended-release formulation, 15 mg/kg should be used) to ensure higher levels of exposure to CLA and an increase in the time above the MIC compared to those achieved with the currently used dose of 7.5 mg/kg once daily.

Physiologically based pharmacokinetic model of mechanism-based inhibition of CYP3A by clarithromycin.

The prediction of clinical drug-drug interactions (DDIs) due to mechanism-based inhibitors of CYP3A is complicated when the inhibitor itself is metabolized by CYP3Aas in the case of clarithromycin. Previous attempts to predict the effects of clarithromycin on CYP3A substrates, e.g., midazolam, failed to account for nonlinear metabolism of clarithromycin. A semiphysiologically based pharmacokinetic model was developed for clarithromycin and midazolam metabolism, incorporating hepatic and intestinal metabolism by CYP3A and non-CYP3A mechanisms. CYP3A inactivation by clarithromycin occurred at both sites. K(I) and k(inact) values for clarithromycin obtained from in vitro sources were unable to accurately predict the clinical effect of clarithromycin on CYP3A activity. An iterative approach determined the optimum values to predict in vivo effects of clarithromycin on midazolam to be 5.3 microM for K(i) and 0.4 and 4 h(-1) for k(inact) in the liver and intestines, respectively. The incorporation of CYP3A-dependent metabolism of clarithromycin enabled prediction of its nonlinear pharmacokinetics. The predicted 2.6-fold change in intravenous midazolam area under the plasma concentration-time curve (AUC) after 500 mg of clarithromycin orally twice daily was consistent with clinical observations. Although the mean predicted 5.3-fold change in the AUC of oral midazolam was lower than mean observed values, it was within the range of observations. Intestinal CYP3A activity was less sensitive to changes in K(I), k(inact), and CYP3A half-life than hepatic CYP3A. This semiphysiologically based pharmacokinetic model incorporating CYP3A inactivation in the intestine and liver accurately predicts the nonlinear pharmacokinetics of clarithromycin and the DDI observed between clarithromycin and midazolam. Furthermore, this model framework can be applied to other mechanism-based inhibitors.

Effects of steady-state clarithromycin on the pharmacokinetics of zolpidem in healthy subjects.

Zolpidem is extensively metabolized by CYP3A4, CYP2C9 and CYP1A2. Previous studies demonstrated that pharmacokinetics of zolpidem was affected by CYP inhibitors, but not by short-term treatment of clarithromycin. The objective of this study was to investigate the effects of steady-state clarithromycin on the pharmacokinetics of zolpidem in healthy subjects. In the control phase, 33 subjects received a single dose of zolpidem (5 mg). One week later, in the clarithromycin phase, the subjects received clarithromycin (500 mg) twice daily for 5 days to reach steady state concentrations, followed by zolpidem (5 mg) and clarithromycin (500 mg). In each phase, plasma concentrations of zolpidem were evaluated up to 12 h after drug administration by using liquid chromatography-tandem mass spectrometry method. In the clarithromycin phase, mean total area under the curve of zolpidem (AUCinf) was 1.62-fold higher and the time to reach peak plasma concentration of zolpidem (tmax) was prolonged by 1.95-fold compared to the control phase. In addition, elimination half-life (t1/2) of zolpidem was 1.40-fold longer during co-administration with clarithromycin and its apparent oral clearance (CL/F) was 36.2% lower with clarithromycin administration. The experimental data demonstrate the significant pharmacokinetic interaction between zolpidem and clarithromycin at steady-state.

The modulation of drug-loading stability within lipid membranes via medium chain triglycerides incorporation.

The current research aimed to explore medium chain triglycerides (MCT) incorporation in liposomes to overcome stability challenges when drugs with high molecular weight and payload are loaded within lipid membranes. A model drug clarithromycin was loaded in lipid dispersions with various MCT/phospholipids ratios (RM/P = 0, 0.5, 1.75 and 7.5 w/w). TEM images demonstrated a liposome-to-emulsion structural transformation by MCT incorporation to cause increased particle size (104.3-167.7 nm) but decreased zeta potential (-63.6 to -44.4 mV) of lipid particles. MCT incorporation produced biphasic release in PBS and accelerated released in plasma. The tolerance of liposomes for thermal sterilization, high temperature test and freeze-thaw cycles were significantly improved by MCT incorporation. However, MCT incorporation produced adverse effects on colloidal stability in plasma and pharmacokinetics behavior in vivo to some extent. MCT stabilizing mechanism attributes to the modulation of drug loading area and stability improvement of lipid carriers. MCT incorporated liposomes achieved 2-3 fold cellular uptake level than traditional liposomes without significant cytotoxicity. These results indicated that MCT incorporation could be a promising strategy to apply in liposome production to achieve stable drug loading.

Darunavir/ritonavir pharmacokinetics following coadministration with clarithromycin in healthy volunteers.

This study investigated the steady-state pharmacokinetic interaction between the HIV protease inhibitor, darunavir (TMC114), administered with low-dose ritonavir (darunavir/ritonavir), and clarithromycin in HIV-negative healthy volunteers. In a 3-way crossover study, 18 individuals received darunavir/ritonavir 400/100 mg bid, clarithromycin 500 mg bid, and darunavir/ritonavir 400/100 mg bid plus clarithromycin 500 mg bid in 3 separate sessions for 7 days, with a washout period of at least 7 days between treatments. Pharmacokinetic assessment was performed on day 7. Safety and tolerability of the study medication were monitored throughout. Coadministration of darunavir/ritonavir with clarithromycin resulted in a reduction in darunavir maximum plasma concentration (Cmax) and area under the curve from administration until 12 hours postdose (AUC12 h) of 17% and 13%, respectively. Ritonavir Cmax and AUC12 h were unchanged. During coadministration with darunavir/ritonavir, clarithromycin Cmax and AUC12 h increased by 26% and 57%, respectively; 14-hydroxy-clarithromycin plasma concentrations were reduced to below the lower limit of quantification (<50 ng/mL). The study medication was generally well tolerated. Based on these pharmacokinetic findings, neither clarithromycin nor darunavir/ritonavir dose adjustments are necessary when clarithromycin is coadministered with darunavir/ritonavir.

Simplified method for determination of clarithromycin in human plasma using protein precipitation in a 96-well format and liquid chromatography-tandem mass spectrometry.

A simplified method to determine clarithromycin concentrations in human plasma using protein precipitation in a 96-well plate and liquid chromatography-tandem mass spectrometry was developed and validated. Plasma proteins were precipitated with acetonitrile and roxithromycin was used as the internal standard. After vortex mixing and centrifugation, the supernatants were directly injected onto a Phenomenex Luna Phenyl-Hexyl column (50 mm x 2.0 mm ID, 3 microm). The mobile phase consisted of water and methanol (30:70, v/v) containing 0.1% formic acid and 5mM ammonium acetate. The flow rate was 0.22 mL/min and the total run time (injection to injection) was less than 3 min. Detection of the analytes was achieved using positive ion electrospray tandem mass spectrometry in selected reaction monitoring (SRM) mode. The linear standard curve ranged from 100 to 5000 ng/mL and the precision and accuracy (inter- and intra-run) were within 7.9% and 4.9%, respectively. The method was successfully used to determine clarithromycin concentrations in human plasma samples obtained from healthy subjects who were given clarithromycin 500 mg for 3 days. The method is rapid, simple, precise and directly applicable to clarithromycin pharmacokinetic studies.

Distribution of systemic clarithromycin to gingiva.

BACKGROUND: Aggressive and recurrent forms of periodontitis are associated with infections by Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans) and Porphyromonas gingivalis. Because these pathogens invade tissue, they are difficult to eliminate by root planing alone. The use of systemic antibiotics in conjunction with root planing significantly enhances clinical and microbiologic treatment outcomes. Although it is not widely prescribed by periodontists, clarithromycin is potentially useful because it is taken up by host cells and has favorable antimicrobial activity. METHODS: Experimental gingivitis was induced in eight healthy subjects at one randomly selected maxillary posterior site. The contralateral maxillary site served as the healthy control. Thereafter, subjects were administered six doses of clarithromycin, 500 mg, every 12 hours. Blood was then drawn, and samples of gingiva were harvested from both sites. The samples were extracted, and clarithromycin content was analyzed by liquid chromatography. RESULTS: Mean clarithromycin concentrations in healthy control and inflamed gingiva (2.4 and 3.0 microg/g, respectively) were significantly higher than in serum (0.5 microg/ml; P <0.05). Clarithromycin levels at control and gingivitis sites were higher than serum by 5.7- and 7.0-fold, respectively (difference between sites was significant; P = 0.02). At control sites, a significant decrease in gingival crevicular fluid flow rate was evident at the conclusion of the clarithromycin regimen (P = 0.018). CONCLUSIONS: Clarithromycin can attain higher levels in gingiva than serum and reach higher levels in inflamed gingiva than in healthy gingiva. Its distribution profile seems to be suitable for the treatment of periodontitis. The reduction in crevicular fluid flow at control sites suggested that clarithromycin may produce anti-inflammatory effects.

Bioavailability of clarithromycin cyclodextrin ternary complexes upon oral administration to healthy beagle dogs.

The dissolution profiles of clarithromycin (CLM) and its beta-cyclodextrin-citric acid ternary complexes (CTC) were examined. CTC showed an enhanced dissolution rate in pH 6.8 phosphate buffers. The relative bioavailability was evaluated by comparing area under the plasma concentration-time curve (AUC) of the pure CLM with that of its cyclodextrin-citric acid ternary complexes those were filled into hard gelatin capsules. To compare the pharmacokinetic behavior, both plasma levels of parent compound and the active metabolite 14-OH-CLM concentrations were estimated. The relative bioavailability value as the ratios of CLM of mean total AUC for CTC relative to CLM was 120.3%. The relative bioavailability value as the ratios of 14-OH CLM of mean total AUC for CTC relative to CLM was 95.3%. The results suggest that the absorption of CTC in beagle dogs was slightly improved because of the enhanced dissolution rate of CTC at pH 6.8.

Determination of clarithromycin in human serum by high-performance liquid chromatography after pre-column derivatization with 9-fluorenylmethyl chloroformate: application to a bioequivalence study.

A sensitive liquid chromatographic method for the analysis of clarithromycin, a macrolide antibiotic, in human serum using pre-column derivatization with 9-fluorenylmethyl chloroformate (FMOC-Cl) is described. The method involved liquid-liquid extraction of the drug and an internal standard (amantadine) followed by pre-column derivatization of the analytes with FMOC-Cl. A mixture of 0.05 M phosphate buffer containing triethylamine (2 mL L(-1); pH 3.8) and methanol (17:83, v/v) was used as mobile phase and chromatographic separation was achieved on a Shimpack CLC-ODS column. The eluate was monitored by a fluorescence detector with respective excitation and emission wavelengths of 265 and 315 nm. The analytical method was linear over the concentration range of 0.025-10 microg mL(-1) of clarithromycin in human serum with a limit of quantification of 0.025 microg mL(-1). The assay is sensitive enough to measure drug levels obtained in human single dose studies. In the present method, sensitivity and run time of analysis have been improved, and successfully applied in a bioequivalence study of three different clarithromycin preparations in 12 healthy volunteers.

Determination of clarithromycin in human plasma by liquid chromatography-electrospray ionization tandem mass spectrometry.

A rapid and sensitive method has been developed for the determination of clarithromycin in human plasma with liquid chromatography-tandem mass spectrometry. Clarithromycin and the internal standard, telmisartan were precipitated from the matrix (50 microl) with 200 microl acetonitrile and separated by HPLC using formic acid:10 mM ammonium acetate:methanol (1:99:400, v/v/v) as the mobile phase. The assay based on detection by electrospray positive ionization mass spectrometry in the multiple-reaction monitoring mode was finished within 2.4 min. Linearity was over the concentration range 10-5000 ng/ml with a limit of detection of 0.50 ng/ml. Intra- and inter-day precision measured as relative standard deviation were <3.73% and <9.93%, respectively. The method was applied in a bioequivalence study of two tablet formulations of clarithromycin.

[Measurement of rifampicin and clarithromycin in serum by high-performance liquid chromatography with electrochemical detection].

Rifampicin (RFP) induces hepatic drug-metabolizing enzymes, making drug interactions a very important clinical problem. Clarithromycin (CAM) metabolism is reportedly enhanced by induction of hepatic drug-metabolizing enzymes (CYP3A4) by RFP, so that the blood lend of CAM decreases when RFP is administered concurrently. We connected an electrochemical detector to a high-performance liquid chromatograph (HPLC) for simple, rapid, easy measurement of blood concentrations of RFP and CAM. Using samples of patient serum, normal serum, and reference standards, we compared HPLC by an external laboratory and the results of LC/MS/MS analysis with those of this new assay. A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels (r=0.975, p<0.01). A strong correlation was also seen between results we obtained for CAM with the electrochemical detector in this assay and values measured by LC/MS/MS analysis (r=0.995, p<0.01). Our method enabled simple, rapid measurement of RFP and CAM by connecting the HPLC and electrochemical detector in tandem. This system was used to modulate dosage during combined therapy with RFP and CAM. The therapeutic effect for nontuberculous mycobacteriosis is expected to improve, and our HPLC is expected to be useful for simple, rapid, easy measurement of blood concentrations.

[Clinical analysis of drug interaction between rifampicin and clarithromycin which are used for treating pulmonary Mycobacterium avium complex infection].

PURPOSE: We reviewed the interaction between rifampicin (RFP) and clarithromycin (CAM) during treatment of pulmonary Mycobacterium avium complex infection. SUBJECTS AND METHODS: The subjects were patients with pulmonary non-tuberculous acid-fast bacillus infection during the period from September 2004 to January 2006 who consented to this study. Drug blood concentrations were compared with the minimum inhibitory concentrations for M. avium isolated from sputum and blood levels of CAM were assessed when the time of administration was changed for RFP. RESULTS: The blood concentration of CAM showed a marked decrease in all cases (n = 6) when administered together with RFP, but there was no significant difference in the blood concentration of 14-R-hydroxy-clarithromycin (M-5), the active metabolite of CAM. However, the total blood concentration of CAM and M-5 showed a significant fall, similar to the blood concentration of CAM alone. When the blood concentration and bacterial MIC were compared for RFP, the blood concentration exceeded five MIC(s) in six samples as did the CAM+M-5 level in four out of six samples. There was no significant difference in the blood concentration of CAM (n = 5) when the time of RFP administration was altered. CONCLUSION; Because the total blood concentration of CAM+M-5 fell markedly by co-administration of RFP, this might have an influence on the antibacterial effect of CAM. In addition, examination of the administration of RFP and CAM at different times showed that the blood concentration of CAM did not increase and the influence of induction of hepatic drug-metabolizing enzymes by RFP could not be avoided.