Unique Pharmacokinetic Parameters with Prolonged Elimination Half-life of...

[Full title: Unique Pharmacokinetic Parameters with Prolonged Elimination Half-life of Oral Azithromycin and Analysis of Pharmacokinetic Phenotype in Young Taiwanese Population]

[Find the meaning and references behind the names: Mono, Files, Chuan, Choice, Hsien, Doi, June, Mei, Wen, Unique, Key, Life, Gene, Normal, Male, Road, Max, Int, Risk, Hospital, Present, Inter, Time, Aimed, September, Chao, Huang, February, Smirnov, Original, Bio, Wei, Oral, Data, Under, Lack, Point, Mackay, Mass, Sec, Open, Last, Junior, Play, Area, Chang, Chen, Non, Author, Tang, Study, Strong, Ming, Yen, Half, Tel, Peak, Infinity, Young]

OPEN ACCESS International Journal of Pharmacology ISSN 1811-7775 DOI: 10.3923/ijp.2018.981.991 Research Article Unique Pharmacokinetic Parameters with Prolonged Elimination Half-life of Oral Azithromycin and Analysis of Pharmacokinetic Phenotype in Young Taiwanese Population 1,2 Wen-Kuei Chang, 2,3 Chao-Hsien Chen, 4 Yen-An Chen, 4 Mei-Chuan Tang, 4 Sy-Yeuan Ju, 4 Szu-Wei Huang and 2,3,5 Kun- Ming Wu 1 Clinical Trial Office, MacKay Memorial Hospital, Taiwan 2 Chest Division, Department of Internal Medicine, MacKay Memorial Hospital, Taiwan 3 Mackay Medical College, Taiwan 4 Protech Pharma services Corporation, Taipei, Taiwan 5 Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan Abstract Background and Objective: Transporter proteins have been well investigated and are known to play significant roles in drug absorption, distribution and excretion. According to previous research, variations in the ATP-binding cassette B 1(ABCB 1) gene likely contributed to inter-individual variability azithromycin pharmacokinetics. This study aimed to investigate the phenotypes of azithromycin pharmacokinetics (PK) in Taiwanese population following oral administration. Materials and Methods: One hundred and seventeen individuals were orally administered 500 mg Zithromax ® (an azithromycin immediate-release capsule). Bio samples were taken at appropriate times. Azithromycin concentration was quantitated by liquid chromatography tandem mass spectrometry. Non-compartmental models were utilized to illustrate azithromycin PK. Results: Using data from the clinical study involving 117 healthy male volunteers, a normal distribution modeling approach was applied. A comprehensive model considering the PK of azithromycin was newly built. Following oral administration of azithromycin, the maximum observed concentration, time to peak concentration, area under the concentration-time curve from time 0 h to last time point (AUC 0-t ) and area under the concentration-time curve from time 0 h to time infinity (AUC 0- 4 ) were found to be 498±196 ng mL G 1 , 2.5 h, 4042±1344 h×ng mL G 1 and 4401±1468 h×ng mL G 1 , respectively The elimination half-life (t 1/2 ) of azithromycin was 84.2±25.8 h. The Kolmogorov-Smirnov's test and quantile plots revealed that the frequency distributions of area under the concentration-time curve (AUC), Peak concentration (C max ) and t 1/2 were mono-modal. Conclusion: The present finding that azithromycin PK parameters exhibited a normal distribution in the Taiwanese population was inconsistent with previous research of ABCB 1 gene polymorphism on PK as no polymorphism-linked effect was observed. Also, population analysis indicated lack of phenotype differences of azithromycin PK in young Taiwanese. The present data revealed a prolonged t 1/2 on the basis of normal distribution of azithromycin PK, implicating a potential increased risk of antimicrobial resistance. This research demonstrate the unique PK parameters of oral azithromycin, indicating the representative PK phenotype in young Taiwanese that can be helpful to choice of antibiotics clinically Key words: Azithromycin, pharmacokinetics, ABCB 1 gene, phenotype, polymorphism Received: February 09, 2018 Accepted: June 23, 2018 Published: September 15, 2018 Citation: Wen-Kuei Chang, Chao-Hsien Chen, Yen-An Chen, Mei-Chuan Tang, Sy-Yeuan Ju, Szu-Wei Huang and Kun- Ming Wu, 2018. Unique pharmacokinetic parameters with prolonged elimination half-life of oral azithromycin and analysis of pharmacokinetic phenotype in young Taiwanese population. Int. J. Pharmacol., 14: 981-991 Corresponding Author: Kun- Ming Wu, Chest Division, Department of Internal Medicine, MacKay Memorial Hospital, Taiwan No. 92, Sec. 2, Zhongshan N. Road, Zhongshan District, Taipei City 10449, Taiwan Tel: +886-2-25433535 Ext. 2257 Copyright: © 2018 Wen-Kuei Chang et al. This is an open access article distributed under the terms of the creative commons attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited. Competing Interest: The authors have declared that no competing interest exists Data Availability: All relevant data are within the paper and its supporting information files.

[Find the meaning and references behind the names: Ich, Human, Board, Western, Standard, Day, Polar, Dose, Single, Body, Bind, Long, Prior, Great, October, Cases, Pump, Germany, Mic, Api, Grade, Blood, High, Age, Patient, Beta, Acid, Bridge, Post, Mean, Due, Baker, Rate, Free, Ion, Aldrich, Louis, Line, Min, Pre, Flow]

Int. J. Pharmacol., 14 (7): 981-991, 2018 INTRODUCTION Azithromycin is an azalide antibiotic categorized as a subclass of the macrolide antibiotic family which can bind to the 50 S ribosomal subunit of susceptible organisms, thereby interfering with protein synthesis. After oral administration of azithromycin, blood concentrations decline in two or three phases with a terminal elimination half-life of over 60 h (h) 1 . It is approved worldwide for treatment of patient with pneumonia, acute sinusitis, uncomplicated skin infection and genital ulcer disease as both intravenous and oral formulations. Due to increasing resistance, azithromycin is more recommended only as a treatment option for pneumonia caused by atypical bacteria or a second-line treatment in cases of life-threatening beta-lactam allergy. One of the possible cause of growing resistance of azithromycin is the long t 1/2 2-5 Previously, azithromycin pharmacokinetic studies were conducted in Japanese subjects and a population pharmacokinetic-pharmacodynamic (PK-PD) analysis approach was implemented to bridge data from Western populations with the Japanese data in accordance with the guidelines of the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use 2 . The results demonstrated that azithromycin exposure was similar between Japanese and Western subjects and that the exposure-efficacy relationship of azithromycin could be characterized by area under the concentration-time curvedivided by the minimum inhibitory concentration(AUC/MIC). For the relationship between the systemic exposure and safety, the incidence of treatment-related diarrhea was positively associated with azithromycin exposure, indicating that adverse drug reaction incidents were linked with higher azithromycin exposure However, the great variations of azithromycin pharmacokinetics, including C max and t 1/2 , were observed from clinical trials in other ethnicities 6-12 , raising concerns about clinical application universally. Therefore, the objective of this study was to investigate azithromycin PK in healthy young Taiwanese subjects as well as the variation in azithromycin PK in these subjects MATERIALS AND METHODS Subjects: These studies were conducted in Mackay Memorial Hospital, a medical center in Taiwan, during May 27, 2012 to October 10, 2014. The study protocol was approved by the Institutional Review Board of Mackay Memorial Hospital. All subjects signed the informed consent. One hundred and seventeen healthy volunteers were enrolled for this study. The clinical characteristics of the volunteers were demonstrated as Mean±Standard Deviation (Mean±SD): Age, 23.5±2.9 years, height, 172.5±6.2 cm and body weight, 65.9±6.3 kg. The volunteers were free from diseases and routine examinations were within reference values Drug administration and blood collection: The study subjects were fasted overnight and orally administered a single 500 mg azithromycin dose with 240 mL water. Zithromax ® was used as the investigation drug. Blood samples (10 mL) were drawn in heparinized tubes prior to dosing (0 h) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 168 (Day 8) and 216 (Day 10) h post administration. After centrifugation, plasma was transferred to pre-labeled tubes and stored at a temperature of -20 E C until further experimentation. The time between blood collection and freezer storage was not greater than 1.5 h. Chemicals and reagents: USP azithromycin was purchased from Rockville (MA, USA). Oxybutynin, which was used as an internal standard (IS), was purchased from Sigma-Aldrich Co. (St. Louis, MO, USA). Acetonitrile (ACN) and methanol (MeOH) were of ChromAR ® grade (Avantor TM Performance Materials, Inc., NJ, USA). Diethyl ether was purchased from J.T. Baker (NJ, USA). Ammonium acetate was purchased from Sigma-Aldrich Chemie GmbH (Seelze, Germany). Formic acid (FA) was of analytic grade from Merck KGaA (Darmstadt, Germany) Chromatographic conditions: The High performance liquid chromatography(HPLC) system (Agilent-1260 infinity series, Wilmington, DE, USA) contained a Binary pump, an autosampler and an Phenomenex ® , Synergi 4 u, Polar-RP 80 A column (75×4.6 mm, 4 µm). Chromatography was performed at 30 E C. The compound was chromatographed on a Phenomenex ® , Synergi, Polar-RP analytical column with a mobile phase composed of 85% mobile phase A and 15% mobile phase B. Mobile phase A was ACN:FA = 100:0.2, mobile phase B was MeOH:H 2 O:FA = 10:90:0.2, flow rate was 1.0 mL min G 1 . The tandem mass spectrometry detection system was assayed using an API 4000 TM model. Ion transition mass divided by charge number(m/z) values for azithromycin and oxybutynin were 749.8-591.7 and 358.5-141.9, respectively 982

[Find the meaning and references behind the names: Range, Less, Fig, Stream, Excellent, Counts, Tube, Sample, Run, Table, Quality, Shown]

Int. J. Pharmacol., 14 (7): 981-991, 2018 Sample preparation: A 200 µL aliquot of human plasma was spiked with 500 µL of acetonitrile with 100 ng mL G 1 IS and was vortexed for 1 min. The mixture was centrifuged at 3,000 rpm for 10 min and the solvent layer was transferred to a clean tube. Then, 50 µL of 1 M CH 3 COONH 4 and 3 mL of diethyl ether were added and vortexed. Centrifugation was performed at 3,000 rpm for 5 min. The organic layer was transferred to a fresh tube and evaporated under a stream of nitrogen. The residues were resolved into 2 mL of mobile phase A and a 10 µL aliquot was injected into the HPLC and subjected to analysis Method validation: The retention times for azithromycin and oxybutynin were 1.82 and 1.44 min (Fig. 1 and 2), respectively. No significant interfering peak was detected as shown in Fig. 3. Azithromycin calibration curves showed a linear relationship over a concentration range of 1-1000 ng mL G 1 . The regression equation for azithromycin was y = 0.0385 x-0.00691 and the correlation coefficient (r 2 ) was 0.9974. The mean relative error ranged from -9.0-7.0% and the coefficients of variance were all less than 5.6%. The within and between-run analysis precision (%coefficient of variation [%CV]) and accuracy (%relative error[%RE]) were determined at azithromycin concentrations of 1, 3, 30, 800 ng mL G 1 . The result of precision and accuracy of within-run analysis test and between-run analysis test for azithromycin quality control samples were shown as below (Table 1 and 2). The result indicated that the liquid chromatography tandem mass spectrometry (LC/MS/MS) method is excellent for the quantitative analysis of azithromycin in plasma Fig. 1(a-b): Representative chromatogram of a plasma sample spiked with a concentration of 1 ng mL G 1 of azithromycin, (a) LLOQ: Azithromycin (standard) 749.800/591.700 Da-sample 3 of 16 from 15.wiff, Area: 1.254 e+003 counts Height: 1.993 e+002 cps RT: 1.82 min and (b) LLOQ: Oxybutynin (IS) (standard) 358.500/141.900 Da-sample 3 of 16 from 15.wiff, Area: 3.929 e+004 counts Height: 1.034 e+004 cps RT: 1.82 min 983 200 150 100 50 0 0.5 1.0 1.5 2.0 2.5 Time (min) In tens ity , cps 0.5 1.0 1.5 2.0 2.5 Time (min) 1.00 e 4 8000.00 6000.00 4000.00 2000.00 0.00 In tens ity , cps (b) (a)

[Find the meaning and references behind the names: Cary]

Int. J. Pharmacol., 14 (7): 981-991, 2018 Fig. 2(a-b): Representative chromatogram of a plasma sample spiked with a concentration of 50 ng mL G 1 of azithromycin, (a) STD 4: Azithromycin (standard) 749.800/591.700 Da-sample 7 of 16 from 15.wiff, Area: 7.472 e+004 counts Height: 1.063 e+004 cps RT: 1.82 min and (b) STD 4: Oxybutynin (IS) (standard) 358.500/141.900 Da-sample 7 of 16 from 15.wiff, Area: 3.744 e+004 counts Height: 9.792 e+003 cps RT: 1.44 min Table 1: Precision and accuracy of within-run analysis test for Azithromycin quality control samples Nominal concentration (ng mL G 1 ) ---------------------------------------------------------------------------------------------------------------------------------------- Items Sample number 1 3 30 800 Within-run 1 1.06 2.92 29.7 786 2 1.03 2.79 30.8 776 3 1.08 3.16 31.5 767 4 1.12 2.95 30.2 857 5 0.964 2.94 32.0 800 6 1.05 3.15 29.2 777 n 6.00 6.00 6.0 6.0 Mean 1.05 2.99 30.6 794.0 SD 0.05 0.14 1.1 33.0 %CV 4.80 4.70 3.6 4.2 %RE 5.00 -0.30 2.0 -0.8 Data analysis: Non-compartmental model was applied to describe the pharmacokinetic properties of azithromycin in the present study and the results were found to correspond with those reported previously 9-14 . Individual azithromycin plasma concentration data were analyzed by the WinNonlin ® (Pharsight, Cary, NC) program. The PK parameters including 984 8000 6000 4000 2000 0 0.5 1.0 1.5 2.0 2.5 Time (min) In tens ity , cps 0.5 1.0 1.5 2.0 2.5 Time (min) 1.00 e 4 8000.00 6000.00 4000.00 2000.00 0.00 In tens ity , cps (b) (a)

[Find the meaning and references behind the names: Double, Blank, Poor, Show, Sas, Median]

Int. J. Pharmacol., 14 (7): 981-991, 2018 Fig. 3(a-b): Representative extracted ion chromatogram (EIC) of a drug-free plasma sample (double blank), (a) Signals for azithromycin and (b) Oxybutamin (IS) were monitored by mass spectrometry with the same detection parameters as in Fig. 1. Wherein x-axis is retention time and y-axis is intensity in cps (counts per second). The scale of y-axis is enlarged to show that no significant interfering peak was existed Table 2: Precision and accuracy of between-run analysis test calibration for Azithromycin quality control samples Nominal concentration (ng mL G 1 ) ---------------------------------------------- --------------------------------------------------------------------------------------------------------------------------- Run numbers 1 RE (%) 3 RE (%) 30 RE (%) 800 RE (%) Between-run 1 1.12 12.0 3.37 12.3 28.6 -4.7 846 5.8 Between-run 2 0.991 -0.9 2.98 -0.7 33.1 10.3 836 4.5 Between-run 3 1.08 8.0 3.00 0.0 28.0 -6.7 788 -1.5 Between-run 4 1.04 4.0 3.06 2.0 30.3 1.0 732 -8.5 Between-run 5 0.960 -4.0 2.62 -12.7 29.5 -1.7 771 -3.6 n 5.00 5.00 5.0 5.0 Mean 1.04 3.01 29.9 795.0 SD 0.06 0.27 2.0 47.0 CV (%) 5.80 9.00 6.7 5.9 RE (%) 4.00 0.30 -0.3 -0.6 C max , t 1/2 , AUC and CL/F were expressed as Mean±SD. The time to achieve peak concentration (T max ) was expressed as median (range). Quantile analysis was used to explore the variation of C max , AUC 0-t , AUC 0- 4 and Dose po /AUC po (CL/F) and were described through normal quantile-quantile plots (Q-Q plots) (Fig. 4-7). The two-sample t-test was used to compare the difference between data of this research and that of other ethnicities. The statistical analysis was to be performed using SAS ® Version 9.2 (SAS-Institute, Cary NC, USA) RESULTS Representative plasma concentration against time profiles for azithromycin is shown in Fig. 8. Azithromycin concentrations were determined in all samples. In previous studies, the methods used to quantify azithromycin concentrations were of limited value because of their poor sensitivity. However, the results indicated that the method developed in this study was suitable for pharmacokinetic studies. The T max , C max , CL/F and t 1/2 were 2.5 1.00-6.00 h, 985 0.5 1.0 1.5 2.0 2.5 Time (min) In tens ity , cps 12.0 10.0 8.0 6.0 4.0 2.0 0.0 (a) 40 30 20 10 0 Time (min) In tens ity , cps (b) 0.5 1.0 1.5 2.0 2.5

Int. J. Pharmacol., 14 (7): 981-991, 2018 Fig. 4: Normal quantile-quantile plot for Cmax of Azithromycin in a young Taiwanese (n = 117) Fig. 5: Normal quantile-quantile plot for AUC 0-t of Azithromycin in a young Taiwanese (n = 117) 498±196 ng mL G 1 , 46.0±17.6 L h G 1 and 84.2±25.7 h, respectively (n = 117). After azithromycin administration, the AUC 0-t and AUC 0- 4 were 4042±1344 h×ng mL G 1 and 4401±1468 h×ng mL G 1 , respectively. The mean ratio of AUC 0-t to AUC 0- 4 was over 80%, which represented a suitable sampling schedule. The extent of variation in oral azithromycin pharmacokinetics in young Taiwanese, it is revealed a prolonged half-life on the basis of normal distribution of 986 1,000 800 600 400 200 0 -200 0 250 500 750 1,000 1,250 Observed value Expe cte d nor m al Mean 498 Std. Deviation 196 K-S 0.063 p >0.150 8,000 6,000 4,000 2,000 0 0 2,000 4,000 6,000 8,000 Observed value Expe cte d nor m al Mean 4042 Std. Deviation 1344 K-S 0.080 p-value = 0.064

Int. J. Pharmacol., 14 (7): 981-991, 2018 Fig. 6: Normal quantile-quantile plot for AUC 0-8 of Azithromycin in a young Taiwanese (n = 117) Fig. 7: Normal quantile-quantile plot for CL/F of Azithromycin in a young Taiwanese (n = 117) azithromycin pharmacokinetics. Normality tests, agglomerative hierarchical clustering and non-hierarchical K-means clustering were performed using AUC 0‒t data. No distinct phenotypes were identified, which was an unexpected result. Figure 4-7 show normal Q-Q plots with the results of the K-S tests for azithromycin C max , AUC 0‒t , AUC 0‒ 4 and CL/F, respectively. Briefly, theresults could not identify any polymorphism on azithromycin PK characteristics 987 10,000 8,000 6,000 4,000 2,000 0 0 2,000 4,000 6,000 8,000 10,000 Observed value Expe cte d nor m al Mean 4401 Std. Deviation 1468 K-S 0.088 p-value = 0.026 100 80 60 40 20 0 0 50 100 150 Observed value Expe cte d nor m al Mean 46.0 Std. Deviation 17.6 K-S 0.103 p<0.01

[Find the meaning and references behind the names: Chinese, Future, Role]

Int. J. Pharmacol., 14 (7): 981-991, 2018 1000 100 10 1 0 50 100 150 200 C o ncen tr atio n ( n g mL ) G 1 Time (h) Fig. 8: Representative plasma concentration-time curves for azithromycin DISCUSSION In present study, azithromycin pharmacokinetic parameters exhibited a normal distribution and ABCB 1 genetic polymorphism influence on azithromycin pharmacokinetics was not observed in young Taiwanese. This observation was unexpected. Previous research indicated that azithromycin pharmacokinetic parameters exhibited great variability between individuals with ABCB 1 genotypes 15 . A number of single nucleotide polymorphisms (SNPs) have been identified for the ABCB 1 gene. Three SNPs, 1236 C>T, 2677 G>T and 3435 C>T, were discovered and demonstrated to affect P-glycoprotein (P-gp) expression levels and function. The frequencies at which these polymorphisms exist within a population have been shown to be linked to ethnicity 16 Clinical studies have been conducted to investigate the association between such polymorphisms and the expression and function of P-gp as well as the pharmacokinetics of its substrates 15 . These SNPs may be the underlying cause of the aforementioned variation in azithromycin pharmacokinetics It had been reported that drug transporter geneticpolymorphisms affect pharmacokinetics as well as drug pharmacological and toxicologicaleffects. Previous reports showed that azithromycin pharmacokinetics may be influenced by particular polymorphisms of the ABCB 1 gene In the Chinese population, the SNP at 3435 C>T played a significant role in the ABCB 1 gene and pharmacokinetic parameters also exhibited great variability between the 2677 GG/3435 CC, 2677 GT/3435 CT and 2677 TT/3435 TT groups 15 . Haplotype and genotype analysis from these data may be used as a basis for future studies on the relationship between ABCB 1 genotypes and drug efficacy, drug toxicity, disease susceptibility or other phenotypes The highest frequencies of the three aforementioned SNPs of the ABCB 1 gene were exhibited in Asian and Caucasian populations, with the lowest in African populations 17 . Pharmacokinetic parameters such as T max , t 1/2 and AUC 0‒ 4 have all been highly variable among published studies. The Taiwanese population was also shown to possess ABCB 1 SNPs (C 3435 T, G 2677 T and C 1236 T) 18,19 but the impact of ABCB 1 polymorphisms on azithromycin has not been investigated. Azithromycin is also a substrate for numerous transporter systems. Co-administration with a transporter inhibitor or inducer resulted in altered azithromycin pharmacokinetic parameters, including C max and AUC. The results of previous animal studies demonstrated that azithromycin administration with organic anion transporting polypeptide (OATP) inhibitors significantly decreased the C max and AUC of azithromycin 20 Although most nucleotide variants are located within the coding regions of the OATP gene, no SNPs were discovered in the young Taiwanese 21 . Thus, variations in the promoter region may account for inter-individual differences in OATP expression, enzymatic activity as well as placental and hepatic mRNA levels. Further studies taking into 988

[Find the meaning and references behind the names: Ahmed, Thai, Brain, Enough, Samiullah, Liver, Large, Might, Alter, Gandhi, Shorter, Full, Lower, Small, Short]

Int. J. Pharmacol., 14 (7): 981-991, 2018 Table 3: Comparison of azithromycin pharmacokinetic parameters in healthy volunteers from different ethnicities Parameters ----------------------------------------------------------------------------------------------------------------------------------------------------------------------- Dosage C max AUC 0-t AUC 0- 4 Population (n) (mg) T max (h) (ng mL G 1 ) (h×ng mL G 1 ) (h×ng mL G 1 ) t 1/2 (h) References Thai (14) 500 1.5±0.4 425±198 4027±1839 4027±1839 28.1±13.1 Boonleang et al 9 Chinese (24) 500 2.1±0.5 448±102 4308±1236 4986±1553 42.3±12.6 Chen et al 7 Chinese (18) 500 1.9±0.6 566±208 4536±1019 5243±1257 50.0±5.0 Chen et al 6 Germany (24) 500 3.0±0.9 304±344 4365±1936 Beringer et al 10 Indonesian (18) 500 2.0 420 4276 5578 51.0 Setiawati et al 11 Indian (24) 500 4.8±1.0 392±190 6293±9670 7023±9610 41.2±6.4 Ahmed et al 12 Pakistani (12) 500 2.91 380±400 2850±4800 8.8±1.0 Samiullah et al 8 Taiwanese (117) (present study) 500 2.5 498±196 4042±1344 4401±1468 84.2±25.7 consideration of such factors are required for a full understanding of azithromycinpharmacokinetic activity Transporter proteins have been well investigated and are known to play significant roles in drug absorption, distribution and excretion 22 . Azithromycin is a substrate for P-gp, the product of the ABCB 1 gene. P-gp was initially identified owing to its over expression in human tumor cells 23 . It was subsequently found in various non-neoplastic human tissues, including the small and large intestinal epithelium, adrenal gland, placenta, kidney, liver, pancreas and capillary endothelial cells in the brain and testes. Moreover, P-gp is located on the apical or luminal surface of the epithelial cells of the aforementioned tissues or organs 24-27 Previous studies have reported the PK characteristics of azithromycin to be dose dependent. However, the variability in azithromycin PK characteristics has not been exhaustively discussed. In this study, azithromycin was rapidly absorbed and reached T max at 2.5 h after administration. The C max was 498±196 ng mL G 1 and AUC 0-t was 4042±1344 h×ng mL G 1 These results were similar to previous results obtained in Chinese and Thai populations (Table 3) The t 1/2 of azithromycin was 84.2±25.7 h in the present study. However, the t 1/2 of azithromycin ranged from 8.8 to 51 h in previous studies. The factors affecting the plasma half-life of azithromycin could be complex. The sensitivity of the analytical methods, duration of blood sampling and individual variation might also alter pharmacokinetic results. After azithromycin administration, plasma concentrations at 72 h were under 10 ng mL G 1 . Bioanalytical methods with lower limit of quantification (LLOQ) values of 1-50 ng mL G 1 varied, some of them were not sensitive enough to detect the drug in the elimination phase. The sampling duration of single oral doses of azithromycin ranging from 48-120 h was investigated but is was unable to estimate the terminal t 1/2 because of a short duration of blood sampling. Chen et al . developed a specific assay for azithromycin with a LLOQ of 1 ng mL G 1 , which was a significant improvement over previous methods and this validated bioanalytical method has also been applied in pharmacokinetic studies 6,7,28 . A similar result was obtained and it is similar to the reported pharmacokinetic parameters with the same dosage form and dosage with a longer half-life, indicating that these improvements in assay sensitivity resulted in similar results to those obtained by Gandhi et al 29,30 . Analytical methods with significant improvements in sensitivity also enabled longer plasma concentration-time profiles for azithromycin. Sufficient duration of blood sampling is required for the adequate calculation of the terminal elimination rate to compute profiles 29,30 . Samiullah et al 8 reported azithromycin pharmacokinetics in Pakistani volunteers at 48 h after drug administration and found a t 1/2 of 8.8 h, which was shorter than that reported previously. Taken together, these data indicate that blood sampling should be continued for at least 120 h during azithromycin pharmacokinetic studies in order to capture the complete plasma-concentration profile and the true elimination half-life. Unfortunately, the prolonged t 1/2 could be also the risk of higher resistant rate in terms of clinical practice as it could result in the emergence of resistant strains due to the subinhibitory concentrations at tissue sites over an extended period of time 4,5 This study has several limitations. Since the pharmacodynamics characteristics was not analyzed, including AUC/MIC, the details of antimicrobial effect of azithromycin was not evaluated in this study. More data should be collected, even be combined with clinical practice and research on patients, to explore the benefit of clinical application of azithromycin CONCLUSION According to previous research, variations in the ATP-binding cassette B 1 gene likely contributed to inter-individual variability azithromycin PK. The finding that 989

[Find the meaning and references behind the names: Liu, Ahmad, Kimchi, Pharm, Khan, January, Baquero, Europa, Chiba, Child, Islam, Zhao, Rieder, Clin, Liang, Han, Sci, Qin, Development, Iqbal, Shah, Mustafa, London, Shohag, Blind, Sun, Peters, Tablet, Rep, Scavo, Ther, Ema, Huynh, Rat, Zheng, Muto, Ling, Zhou, Link, Friedel, Label, Schmidt, Jen, Karim, Bangladeshi, Deng, Qiu, Common]

Int. J. Pharmacol., 14 (7): 981-991, 2018 azithromycin PK parameters exhibited a normal distribution in the Taiwanese population was therefore inconsistent with previous research of ABCB 1 gene polymorphism on PK as no polymorphism-linked effect was observed. Also, population analysis indicated lack of phenotype differences of azithromycin PK in young Taiwanese. The present data revealed a prolonged t 1/2 on the basis of normal distribution of azithromycin PK, implicating a potential increased risk of antimicrobial resistance. This research demonstrate the unique PK parameters of oral azithromycin, indicating the representative PK phenotype in young Taiwanese that can be helpful to choice of antibiotics clinically SIGNIFICANCE STATEMENT This research discovered that there are no significant differences between phenotypes of azithromycin pharmacokinetics in young Taiwanese population. A longer half-life of azithromycin was observed and it indicated that a potential increased risk of antimicrobial resistance in clinical practices ACKNOWLEDGMENT This manuscript was revised by Dr. Yu-Jen Chen REFERENCES 1 Peters, D.H., H.A. Friedel and D. McTavish, 1992. Azithromycin A review of its antimicrobial activity, pharmacokinetic properties and clinical efficacy. Drugs, 44: 750-799 2 Muto, C., P. Liu, K. Chiba and T. Suwa, 2011 Pharmacokinetic-pharmacodynamic analysis of azithromycin extended release in Japanese patients with common respiratory tract infectious disease. J. Antimicrob. Chemother., 66: 165-174 3 Ovetchkine, P., M.J. Rieder and Canadian Paediatric Society, Drug Therapy and Hazardous Substances Committee, 2013 Azithromycin use in paediatrics: A practical overview Paediatr. Child Health, 18: 311-316 4 Baquero, F., 1999. Evolving resistance patterns of Streptococcus pneumoniae : A link with long-acting macrolide consumption? J. Chemother., 11: 35-43 5 Zheng, S., P. Matzneller, M. Zeitlinger and S. Schmidt, 2014 Development of a population pharmacokinetic model characterizing the tissue distribution of azithromycin in healthy subjects. Antimicrob. Agents Chemother., 58: 6675-6684 6 Chen, L., F. Qin, Y. Ma and F. Li, 2007. Quantitative determination of azithromycin in human plasma by ultra performance liquid chromatography-electrospray ionization mass spectrometry and its application in a pharmacokinetic study. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci., 855: 255-261 7 Chen, B.M., Y.Z. Liang, X. Chen, S.G. Liu, F.L. Deng and P. Zhou, 2006. Quantitative determination of azithromycin in human plasma by liquid chromatography-mass spectrometry and its application in a bioequivalence study. J. Pharm. Biomed. Anal., 42: 480-487 8 Samiullah, Z. Iqbal, M.I. Khan, A. Khan, A. Khan Y. Shah and L. Ahmad, 2011. Bioequivalence of 2 azithromycin capsule formulations: A randomized, single-dose, open-label, 2-period crossover study in healthy male pakistani volunteers. Curr. Ther. Res. Clin. Exp., 72: 95-108 9 Boonleang, J., K. Panrat, C. Tantana, S. Krittathanmakul and W. Jintapakorn, 2007. Bioavailability and pharmacokinetic comparison between generic and branded azithromycin capsule: A randomized, double-blind, 2-way crossover in healthy male Thai volunteers. Clin. Ther., 29: 703-710 10. Beringer, P., K.M. Huynh, J. Kriengkauykiat, L. Bi and N. Hoem et al ., 2005. Absolute bioavailability and intracellular pharmacokinetics of azithromycin in patients with cystic fibrosis. Antimicrob. Agents Chemother., 49: 5013-5017 11. Setiawati, E., S.H. Deniati, D.A. Yunaidi, H.L. Rat and G. Harinanto et al ., 2009. Bioequivalence study of two azithromycin formulations in healthy subjects. Arzneimittelforschung, 59: 471-475 12. Ahmed, M.U., M.S. Islam, H. Shohag, R. Karim and A.G.M. Mustafa et al ., 2012. Comparative pharmacokinetic and bioequivalence study of azithromycin 500 mg tablet in healthy Bangladeshi volunteers. Int. J. Clin. Pharmacol. Ther., 50: 452-458 13. EMEA., 2006. Guideline on the role of pharmacokinetics in the development of medicinal products in the paediatric population. European Medicines Agency, London, 28 June 2006. http://www.ema.europa. eu/docs/en̲GB/document̲ library/Scientific̲guideline/2009/09/WC 500003066.pdf 14. EMEA., 2010. Guideline on the investigation of bioequivalence. European Medicines Agency, London, 20 January 2010. http://www.ema.europa. eu/docs/en̲GB/ document̲library/Scientific̲guideline/2010/01/WC 500 070039.pdf 15. He, X.J., L.M. Zhao, F. Qiu, Y.X. Sun and J. Li-Ling, 2009 Influence of ABCB 1 gene polymorphisms on the pharmacokinetics of azithromycin among healthy Chinese Han ethnic subjects. Pharmacol. Rep., 61: 843-850 16. Kimchi-Sarfaty, C., A.H. Marple, S. Shinar, A.M. Kimchi and D. Scavo et al ., 2007. Ethnicity-related polymorphisms and haplotypes in the human ABCB 1 gene. Pharmacogenomics, 8: 29-39 990

[Find the meaning and references behind the names: Lee, Yoshimura, Akiyama, Novotna, Transport, Brambila, Furukawa, Whelan, Schroeder, Nies, Hsu, Kunert, Jiang, Davis, Dawson, Chem, Hosking, Adam, Morgan, Mdr, Ayrton, Metab, Keil, Lines, Major, Ichikawa, Kaul, Tsai, Chim, Cell, Juan, Ruan, Rao, Hou, Tapia, Hill, Lin, Lou, Yang, Chou, Schwab]

Int. J. Pharmacol., 14 (7): 981-991, 2018 17. Brambila-Tapia, A.J., 2013. MDR 1 (ABCB 1) polymorphisms: Functional effects and clinical implications. Rev. Invest. Clin., 65: 445-454 18. Tsai, S.M., C.Y. Lin, S.H. Wu, L.A. Hou, H. Ma, L.Y. Tsai and M.F. Hou, 2009. Side effects after docetaxel treatment in Taiwanese breast cancer patients with CYP 3 A 4, CYP 3 A 5 and ABCB 1 gene polymorphisms. Clin. Chim. Acta, 404: 160-165 19. Chang, H.H., C.H. Chou, Y.K. Yang, I.H. Lee and P.S. Chen, 2015 Association between ABCB 1 polymorphisms and antidepressant treatment response in Taiwanese major depressive patients. Clin. Psychopharmacol. Neurosci., 13: 250-255 20. Garver, E., E.D. Hugger, S.P. Shearn, A. Rao, P.A. Dawson, C.B. Davis and C. Han, 2008. Involvement of intestinal uptake transporters in the absorption of azithromycin and clarithromycin in the rat. Drug Metab. Dispos., 36: 2492-2498 21. Chen, Y.A., C.H. Juan and K.Y. Hsu, 2015. Does ethnic variability exist in the systemic exposures of OATP 1 A 2 substrates-fexofenadine in Taiwanese? Indian J. Pharm. Sci., 77: 573-578 22. Ayrton, A. and P. Morgan, 2001. Role of transport proteins in drug absorption, distribution and excretion. Xenobiotica, 31: 469-497 23. Hill, BT., K. Deuchars, L.K. Hosking, V. Ling and R.D. Whelan, 1990. Overexpression of P-glycoprotein in mammalian tumor cell lines after fractionated X irradiation in vitro . J. Natl. Cancer Inst., 82: 607-612 24. Wolking, S., E. Schaeffeler, H. Lerche, M. Schwab and A.T. Nies, 2015. Impact of genetic polymorphisms of ABCB 1 (MDR 1, P-glycoprotein) on drug disposition and potential clinical implications: Update of the literature. Clin. Pharmacokinet., 54: 709-735 25. Ichikawa, M., A. Yoshimura, T. Sumizawa, N. Shudo, Y. Kuwazuru, T. Furukawa and S. Akiyama, 1991. Interaction of organic chemicals with P-glycoprotein in the adrenal gland, kidney and a multidrug-resistant KB cell. J. Biol. Chem., 266: 903-908 26. Ceckova-Novotna, M., P. Pavek and F. Staud, 2006 P-glycoprotein in the placenta: Expression, localization, regulation and function. Reprod. Toxicol., 22: 400-410 27. Schaarschmidt, T., J. Merkord, U. Adam, E. Schroeder and C. Kunert-Keil et al ., 2004. Expression of multidrug resistance proteins in rat and human chronic pancreatitis. Pancreas, 28: 45-52 28. Jiang, B., J. Chen, Z. Ruan, H. Lou and L. Yu, 2012 Quantification of azithromycin in human plasma by liquid chromatography tandem mass spectrometry: Application to a bioequivalence study. Arzneimittelforschung, 62: 230-235 29. Gandhi, R., C.L. Kaul and R. Panchagnula, 2004 Pharmacokinetic evaluation of an azithromycin controlled release dosage form in healthy human volunteers: A single dose study. Int. J. Pharm., 270: 1-8 30. Gandhi, R., C.L. Kaul and R. Panchagnula, 2000 Validated LC method for in-vitro analysis of azithromycin using electrochemical detection. J. Pharm. Biomed. Anal., 23: 1073-1079 991

Other Health Sciences Concepts:

[back to top]

Discover the significance of concepts within the article: ‘Unique Pharmacokinetic Parameters with Prolonged Elimination Half-life of...’. Further sources in the context of Health Sciences might help you critically compare this page with similair documents:

Sha, Antibiotic, Informed consent, Statistical analysis, Pneumonia, Clinical trial, High performance liquid chromatography, Drug Absorption, Clinical Practice, Normality test, Azithromycin, Clinical application, Antimicrobial Resistance, Institutional review board, Mass spectrometry, Chromatogram, Retention time, Single nucleotide polymorphism, Drug efficacy, Mobile phase, Pharmacokinetic properties, Blood collection, Liquid chromatography-tandem mass spectrometry, Internal standard, Sample preparation, Calibration curve, Normal Distribution, Cmax, Tmax, International Conference on Harmonization, Method validation, Plasma concentration, Formic acid, Elimination half life, Acetonitrile, Precision and accuracy, Pharmacokinetic studies, Drug toxicity, P-glycoprotein, Protein synthesis, Bioanalytical method, Ammonium acetate, Blood sample, Two-sample T-test, Skin infection, Diethyl ether, Plasma half life, Acute sinusitis, Pharmacokinetic Parameter, Western population, Blood concentration, Quantile-quantile plot, Azithromycin resistance, Transporter protein, Drug reaction, Genital ulcer disease, Human tumor cell, Oral azithromycin, Pakistani volunteers, Taiwanese population, Plasma concentration data, Healthy volunteer, PK parameter, WinNonlin, Mackay Memorial Hospital.