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amoxicillin, and cefixime. 4 , 6. Chemically, amlodipine (AML) belongs to the same family of dihydropyridine derivatives as nifedipine. It has physicochemical ...
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JCPXXX10.1177/0091270011435327Di

ng et alThe Journal of Clinical Pharmacology 2012

Effects of Amlodipine on the Oral Bioavailability of Cephalexin and Cefuroxime Axetil in Healthy Volunteers

The Journal of Clinical Pharmacology 53(1) 82–86 © The Author(s) 2012 DOI: 10.1177/0091270011435327

Yi Ding, MM1*, WenXing Liu, MM1*, YanYan Jia, MD1, ChengTao Lu, MD1, Xin Jin, MD1, Jing Yang, MM1, YanRong Zhu, MM1, Lin Yang, MM1, Ying Song, MM1, LiKun Ding, MM1, and AiDong Wen, MD1

Abstract In this study, the authors compared the effects of amlodipine (AML) on the bioavailability of cephalexin (LEX) and cefuroxime axetil (CXM). Twenty-four healthy men were randomized to 4 treatments according to a crossover design with a 14-day washout. After an overnight fast, they were administered orally LEX 500 mg alone, LEX 500 mg 2 hours after oral administration of AML 5 mg, CXM 500 mg alone, and CXM 500 mg 2 hours after oral administration of AML 5 mg. All participants completed the whole study without side effects being observed. Pharmacokinetic data were analyzed by noncompartmental modeling with WinNonlin software. The geometric mean (GM) ratios were 1.38 (90% confidence interval [CI], 1.32-1.45) for the area under the concentration-time curve (AUC) for LEX and 1.27 (1.18-1.36) for the maximum concentration of drug in serum (Cmax) for LEX followed by AML versus alone. In contrast, no significant differences were found in the pharmacokinetic parameters of CXM between treatments (P < .05). They authors conclude that AML possesses an enhancement effect in β -lactam antibiotic bioavailability (in this case, LEX), and this interaction may be specific to the peptidomimetic β -lactam antibiotics.

Keywords amlodipine , β -lactam antibiotics, interaction, bioavailability, healthy volunteers

Many β-lactam antibiotics are transported by the intestinal peptide carrier-mediated transport system that consists of the H+/oligopeptide transporter, PEPT1.1,2 Probably by stimulating PEPT1,3,4 nifedipine, a dihydropyridine Ca2+ antagonist, may have the potential to produce clinically significant enhancement of bioavailability of several β-lactam antibiotics, such as cephalexin,5 amoxicillin, and cefixime.4,6 Chemically, amlodipine (AML) belongs to the same family of dihydropyridine derivatives as nifedipine. It has physicochemical properties similar to nifedipine as well.7 Accordingly, by mechanisms similar to nifedipine, AML may reasonably be expected to enhance some β-lactam bioavailability. There is the potential for clinical benefit if indeed AML enhances β-lactam bioavailability. Furthermore, we hypothesize that the effect may vary in kinds of β-lactam antibiotics because some of them are not substrates of PEPT1.8 As a result, our study involved 2 kinds of β-lactam antibiotics: cephalexin (LEX), a peptidomimetic compound almost exclusively transported by the peptide transporter with practically no additional passive entry in the mammalian intestine,9 and cefuroxime axetil (CXM), the prodrug of cefuroxime, which is deesterified in the intestinal mucosa and absorbed into the bloodstream without involvement of peptide transporters.8,10

In this 4-way, crossover study in 24 healthy male volunteers, we investigated the effects of AML on the bioavailability of 2 different β-lactam antibiotics. We also determined whether this interaction, if any, is related to the structural characterization of β-lactam antibiotics.

Materials and Methods Participants. Twenty-four healthy male volunteers between ages 25 and 45 years and with body mass indexes between 19 and 25 kg/m2 were eligible for enrollment after informed consent forms were signed. All participants were determined to be in good health on the basis of medical history, results of physical examinations, routine laboratory tests, and electrocardiogram (ECG) findings. 1

Xijing Hospital of the Fourth Military Medical University, Xian, China

*These authors contributed equally to the completion of this study and the writing of this article. Submitted for publication 28-Aug-2011; accepted 12-Dec-2011 Corresponding Author: AiDong Wen, MD, Department of Pharmacy, Xijing Hospital of the Fourth Military Medical University, ChangLe West Rd #15, Xian 710032, China Email: [email protected]

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Ding et al They were excluded from study participation if they had donated blood or had participated in a clinical trial with an investigational drug within 90 days of study initiation. Regular heavy drinkers, smokers of more than 10 cigarettes per day, and those with a body weight differing by more than 20% from their ideal weight were also excluded. Study Design. This was an open, randomized, singledose, 4-way, crossover study in 24 healthy male volunteers. The study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. The protocol (Ethics Approval No. 2010L01741) was approved by the Institutional Review Board of Xijing Hospital, Xian, China. Participants were randomized to receive each of 4 dosing regimens separated by a washout period of 14 days. The 4 regimens were as follows: LEX 500 mg (250 mg per capsule; Harbin Pharmaceutical Group Co, Harbin, China) alone; LEX 500 mg, 2 hours after the administration of a single oral dose of AML 5 mg (5 mg per tablet, Pfizer Pharmaceuticals Ltd, Shanghai, China); CXM 500 mg (250 mg per capsule, Glaxo Wellcome UK Ltd, Brentford, UK) alone; and CXM 500 mg, 2 h after the administration of a single oral dose of AML 5 mg. All study medication was swallowed without chewing with 200 mL of water. Participants fasted from 8 hours the night prior to each dosing session. Food was restricted until 3 hours after LEX or CXM dosing when a light standard meal was provided. Participants abstained from smoking, alcohol, caffeine-containing drinks, and grapefruit juice from 48 hours prior to the study start until 48 hours after dosing on each dosing day. Blood Sampling and Analysis. Participants were instructed to remain in a sitting or standing position for at least 2 hours after each dose throughout the study. Blood samples (approximately 3 mL) were taken at 0, 10, 20, 30, and 45 minutes and 1, 1.5, 2, 2.5, 4, 5, 6, and 8 hours after administration for cephalexin, as well as at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours for cefuroxime, through an indwelling angiocatheter inserted into a vein in the forearm. Each sample was collected into a heparin Vacutainer tube and centrifuged immediately for 10 minutes at 6000 rpm. All samples were frozen at –80°C until analysis. The LEX and CXM concentrations were determined using modified high-performance liquid chromatography (HPLC) methods11,12 with an Agilent 1200 HPLC system (Agilent, Munich, Germany). Chromatographic separation was performed on a Diamonsil C18 column (particle size 250 × 4.6 mm, 5 µm). The calibration curves of the methods were linear over a serum concentration range of 0.30 to 50.00 µg/mL for LEX and 0.10 to 20.00 µg/mL for CXM. The lower limits of quantification were 0.30 µg/mL for LEX and 0.10 µg/mL for CXM. For the methods, intra- and interday accuracy and precision were assessed by the use of quality control standards, with

limits for accuracy of 10% and coefficient of variability for precision of 5%. The stock solutions were stable at –20°C for 6 months in 100% methanol. Safety Evaluation. Safety variables assessed included adverse events (AEs), laboratory test results (hematology, clinical chemistry, and urinalysis), vital sign measurements (systolic and diastolic blood pressure, respiration rate, heart rate, and oral body temperature), and electrocardiograms. Adverse events were graded as mild, moderate, severe, or life threatening. The investigators assessed the relationship of any AE to study drug use as unlikely related, possibly related, or probably related. Pharmacokinetic and Statistical Analysis. Pharmacokinetic data were analyzed using a noncompartmental method with the aid of WinNonlin version 6.2 software (Pharsight Corporation, Mountain View, California). The maximum concentration (Cmax) and the time to Cmax (tmax) were obtained directly from the original data. The terminal rate constant (ke) was obtained by regression analysis of the log-linear portion of the concentration-time curve. The terminal half-life (t1/2) was calculated as 0.693/ke. The area under the plasma concentration-time curve (AUC) to the last quantifiable concentration (AUC0-t) was determined by use of the linear trapezoidal rule. AUC from zero to infinity (AUC0-∞) was calculated by AUC0-t + Ct/ke, where Ct is the last measured plasma concentration. The data are expressed as mean ± standard deviation (SD). Derived log-transformed pharmacokinetic parameters (AUC0-∞, Cmax, and t1/2) were statistically analyzed using 2-way analysis of variance (ANOVA; subjects and treatments). The between-treatment tmax data were compared by use of the Wilcoxon signed rank test. Point estimates and 90% confidence intervals (90% CIs) were calculated to compare the treatments. Any value of P below .05 was considered significant. Statistical analyses were performed using SPSS 17.0 (SPSS, Inc, an IBM Company, Chicago, Illinois). For sample size calculations in this study, it was assumed that the coefficient of variation (CV) would range from 20% to 40% for the AUC0-∞ of LEX and CXM. Therefore, a sample size of 20 would provide >90% power to detect a 25% change in the AUC0-∞ of LEX and CXM. The investigation was performed in men because there have been no reports of gender-specific differences in LEX and CXM pharmacokinetics.

Results A total of 24 Chinese men were enrolled into the present study. Demographics were as follows. The mean age was 34.4 ± 4.2 years, the mean weight was 64.6 ± 2.9 kg, and the body mass index was 21.9 ± 1.1 kg/m2. All participants completed the study and tolerated the protocol well. No adverse event was reported in any of

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The Journal of Clinical Pharmacology / Vol 53 No 1 (2013)

Table 1. Pharmacokinetic Parameters (Mean ± SD) of LEX Alone, LEX Plus AML, CXM Alone, and CXM Plus AML (n = 24) Parameter t1/2, h Cmax, μg/mL tmax, h AUC0-∞, μg·h/mL

LEX

LEX + AML

GM Ratio (90% CI)

1.2 ± 0.4 16.6 ± 2.5 1.1 ± 0.4 36.7 ± 6.6

1.6 ± 0.7 21.0 ± 3.7 1.2 ± 0.5 51.3 ± 9.6

1.25 (0.98-1.52) 1.27a (1.19-1.36) 1.10 (0.99-1.20) 1.38a (1.32-1.45)

CXM

CXM + AML

1.8 ± 0.7 7.8 ± 1.5 1.8 ± 0.3 27.3 ± 7.0

1.6 ± 0.5 7.9 ± 1.6 1.9 ± 0.4 27.4 ± 6.8

GM ratio (90% CI) 0.97 (0.84-1.11) 1.01 (0.96-1.07) 1.06 (0.96-1.16) 1.01 (0.97-1.04)

Abbreviations: AML, amlodipine; CI, confidence interval; CXM, cefuroxime axetil; GM, geometric mean; LEX, cephalexin. Values statistically different (P < .05).

a

the volunteers. No statistically significant changes or abnormalities were reported in hematology or clinical chemistry laboratory values, urinalysis, vital signs, or ECG parameters. Pharmacokinetic parameters of LEX and CXM after single dose or combined with the AML dose are given in Table 1. The plasma concentration-time curves of LEX and CXM in all treatments are shown in Figures 1 and 2. After administration of AML, the geometric mean (GM) ratio was 1.38 (90% CI, 1.32-1.45) for AUC and 1.27 (1.18-1.36) for Cmax for LEX followed by AML versus alone (P < .05). The mean t1/2 of LEX was prolonged by 25% in the presence of AML compared with LEX alone. However, this change between 2 treatments was not statistically significant (P > .05). Meanwhile, the tmax of LEX administration following AML was similar to that of LEX administered alone (P > .05), with the mean value at 1.2 hours. With regard to CXM, after a single dose of AML, no significant differences were observed in pharmacokinetic parameters (P > .05).

Figure 1. Cephalexin (LEX) mean concentration-time profiles (± standard deviation) in the absence (open circles) and (filled circles) presence of amlodipine (AML).

Discussion In the present study, after a 500-mg oral dose of LEX or CXM to healthy men, pharmacokinetic parameters of drugs were similar to those reported in previous studies.13,14 Importantly, we observed a statistically significant increase in bioavailability (Cmax and AUC0-∞) of LEX when combined with AML compared with when LEX was dosed alone, whereas t1/2 and tmax of LEX remained unchanged. However, the pharmacokinetic parameters of CXM were not modified when combined with AML. Presumably, the differential effects of AML on the pharmacokinetic parameters of LEX and CXM may be attributable to the differences in the drugs’ chemical structures. In our study, the findings in AML were consistent with similar studies in calcium channel blockers. For example, in rats, it was found that acute and chronic oral administration of nifedipine significantly increased oral LEX AUC (34% and 25%, respectively) and Cmax (57% and 51%, respectively), whereas the elimination parameter

Figure 2. Cefuroxime axetil (CXM) mean concentration-time profiles (± standard deviation) in the absence (open circles) and (filled circles) presence of amlodipine (AML).

was not affected.5 Besides, human studies have shown that nifedipine increases both the absorption rate and the bioavailability of cefixime, a substrate for PEPT1, without modifying its distribution or elimination.6 The absolute bioavailability of cefixime alone was 31% ± 6%

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Ding et al compared with 53% ± 1% (P < .01) in the presence of nifedipine.6 For another β-lactam antibiotic, amoxicillin, which is also absorbed by the dipeptide transport system, similar observations have been reported by Westphal et al.4 Calcium channel blockers significantly enhance both absorption rate (by 70%) and bioavailability of amoxicillin (by 21.4%).4 On the basis of the studies mentioned above, we found that the extent of AML-LEX interaction is similar to that of a nifedipine–β-lactam antibiotics interaction. However, compared with that of other Ca2+ antagonists, AML is more long-acting15 and has the combined advantage of a good safety profile with oncedaily dosage.16 Therefore, AML has the potential to replace nifedipine as an absorption enhancer in the future. As for the uptake in β-lactam antibiotic bioavailability by Ca2+ antagonists, several mechanisms might be involved: (1) by increasing the effect of Ca2+ antagonists on mesenteric blood flow,17 thus favoring passive absorption (provided that transmembrane passage is not a limiting factor); (2) by slowing the movement of fluid through the gut,18 thus allowing more time for absorption to occur; and (3) by stimulating the dipeptide transport system, through the mechanism of uptake in transmembrane Na+-H+ ion exchanges3 or through a complex neural regulation.19 Recently, certain dihydropyridine calcium antagonists were clarified to be inhibitors of P-glycoprotein, which is an efflux transporter in the intestine.20 This might be another possible stimulation of drug uptake. In our study, there was no significant difference found in pharmacokinetics between CXM and CXM-AML treatments. A previous study on comparing the effects of nifedipine and diltiazem on the uptake of cefpodoxime proxetil found no significant difference in pharmacokinetic parameters between the treatment groups.21 Like CXM, cefpodoxime proxetil is not a peptidomimetic drug with particular low affinity for PEPT 1.8 As a result, we assume that the absorption of β-lactam not belonging to the family of peptidomimetic drugs, such as CXM, could not be enhanced by stimulating PEPT 1. They were more likely affected by the gastric environment and other factors. Good absorption of CXM requires a sufficiently low gastric pH,22 but AML seems not to produce a marked effect. Interestingly, AML had no effect on the pharmacokinetics of CXM. The reason may be that, as a lipophilic drug, which passively diffuses across the intestinal epithelium, CXM is apparently dependent on mesenteric blood flow. Our results, combined with a previous study,21 indicate that the AML-LEX interaction may depend on the structure of the individual antibiotic. Moreover, our results strengthen the hypothesis that the absorptionpromoting effect of calcium channel blockers on antibiotics could be attributed to a direct action on brush-border dipeptide carrier activity rather than to a change in the splanchnic circulation rate.3

The present study had several limitations. First, in our study, only a single dose of AML was used. Accordingly, it is unknown whether the effect would persist when the AML was dosed to steady state. Second, we chose 2 hours as a staggered administration interval to evaluate the interaction because AML has a longer tmax (6-7 hours) than LEX and CXM (1-2 hours). However, we did not assess the effects with other administration intervals. Third, the dose of AML used in our study was based on the normal dose in clinical studies. Thus, it remains unknown whether there is a dose-related effect. Fourth, only 2 kinds of β-lactam antibiotics were taken into account. Last, although AML was found to possess significant antimicrobial action and be synergistic in action with streptomycin,23,24 the antimicrobial effect of the AML-LEX combination was not evaluated. More studies are needed to establish this combination in the clinical application. In summary, the data presented in this study demonstrated a significant enhancement in LEX bioavailability by AML. This effect may be specific to the peptidomimetic drug. Becuase LEX has been used as a probe of peptide transporters, other peptidomimetic drugs might benefit from AML treatment, including β-lactam antibiotics,1,2 selected immunostimulants, and angiotensin-converting enzyme inhibitors.25-27 Therefore, further studies on Ca2+ antagonist–β-lactam interactions may help to better understand some of the regulatory processes involved in the control of the intestinal absorption of peptidomimetic drugs. Acknowledgments The authors thank members of the nursing and research staff who participated in the clinical studies. The authors also thank the editor in chief, Dr Daniel S. Sitar, and 2 anonymous reviewers for detailed and constructive comments that greatly improved the manuscript.

Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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