Do dietary interventions exert clinically important effects on the bioavailability of ß-lactam antibiotics? A systematic review with meta-analyses.

BACKGROUND: Managing drug-food interactions may help to achieve the optimal action and safety profile of ß-lactam antibiotics. METHODS: We conducted a systematic review with meta-analyses in adherence to PRISMA guidelines for 32 ß-lactams. We included 166 studies assessing the impact of food, beverages, antacids or mineral supplements on the pharmacokinetic (PK) parameters or PK/pharmacodynamic (PK/PD) indices. RESULTS: Eighteen of 25 ß-lactams for which data on food impact were available had clinically important interactions. We observed the highest negative influence of food (AUC or Cmax decreased by >40%) for ampicillin, cefaclor (immediate-release formulations), cefroxadine, cefradine, cloxacillin, oxacillin, penicillin V (liquid formulations and tablets) and sultamicillin, whereas the highest positive influence (AUC or Cmax increased by >45%) for cefditoren pivoxil, cefuroxime and tebipenem pivoxil (extended-release tablets). Significantly lower bioavailability in the presence of antacids or mineral supplements occurred for 4 of 13 analysed ß-lactams, with the highest negative impact for cefdinir (with iron salts) and moderate for cefpodoxime proxetil (with antacids). Data on beverage impact were limited to 11 antibiotics. With milk, the extent of absorption was decreased by >40% for cefalexin, cefradine, penicillin G and penicillin V, whereas it was moderately increased for cefuroxime. No significant interaction occurred with cranberry juice for two tested drugs (amoxicillin and cefaclor). CONCLUSIONS: Factors such as physicochemical features of antibiotics, drug formulation, type of intervention, and patient's health state may influence interactions. Due to the poor actuality and diverse methodology of included studies and unproportionate data availability for individual drugs, we judged the quality of evidence as low.

Exploring the pharmacokinetics of second-generation cephalosporin, cefaclor: a systematic review in healthy and diseased populations.

Cefaclor is a bactericidal antibiotic recommended for treating diverse types of infections. This review aims to comprehensively assess the pharmacokinetic (PK) data on cefaclor in humans.Google Scholar, PubMed, Cochrane Library, and EBSCO databases were systematically performed to identify all the relevant studies containing at least one reported PK parameter of cefaclor.Cefaclor shows the linear PK profile as the area under the plasma concentration-time curve from 0 to t (AUC0-t) and maximum plasma concentration (Cmax) increase in a dose-dependent manner. The AUC0-t of cefaclor in the rice diet was found to be higher than that of bread food, i.e. 19.9 ± 2.6 ug/ml.hr vs 15.4 ± 4 ug/ml.hr. The AUC in paediatrics during the fed state was significantly higher compared to that in adults. Patients with renal impairments showed a Cmax 2.2 times higher than that of normal subjects. A significant increase in Cmax was depicted among individuals following a vegetarian diet in comparison with the non-vegetarian diet. Moreover, cefaclor exhibits time-dependent killing above the minimum inhibitory concentration (MIC < 2 ug), favouring its use in treating infections caused by specific pathogens.This systematic review summarises all the reported PK parameters of cefaclor in healthy and diseased subjects in the literature. This data can help practitioners in adjusting cefaclor doses among different diseases and populations to avoid drug interactions and adverse effects.

Effects of cranberry juice on pharmacokinetics of beta-lactam antibiotics following oral administration.

Cranberry juice consumption is often recommended along with low-dose oral antibiotics for prophylaxis for recurrent urinary tract infection (UTI). Because multiple membrane transporters are involved in the intestinal absorption and renal excretion of beta-lactam antibiotics, we evaluated the potential risk of pharmacokinetic interactions between cranberry juice and the beta-lactams amoxicillin (amoxicilline) and cefaclor. The amoxicillin-cranberry juice interaction was investigated in 18 healthy women who received on four separate occasions a single oral test dose of amoxicillin at 500 mg and 2 g with or without cranberry juice cocktail (8 oz) according to a crossover design. A parallel cefaclor-cranberry juice interaction study was also conducted in which 500 mg cefaclor was administered with or without cranberry juice cocktail (12 oz). Data were analyzed by noncompartmental methods and nonlinear mixed-effects compartmental modeling. We conclude that the concurrent use of cranberry juice has no significant effect on the extent of oral absorption or the renal clearance of amoxicillin and cefaclor. However, delays in the absorption of amoxicillin and cefaclor were observed. These results suggest that the use of cranberry juice at usual quantities as prophylaxis for UTI is not likely to alter the pharmacokinetics of these two oral antibiotics.

Biodegradable microspheres based on gelatin-porcine mucin admixtures: in vitro and in vivo delivery studies.

Soluble mucus glycoprotein (S-mucin) processed from the small intestines (ileal region) of freshly slaughtered pigs via homogenization, dialysis, centrifugation and lyophilization and their admixtures with type B gelatin were used to prepare cefaclor-loaded microspheres by the emulsification-crosslinking method. The microspheres were evaluated for the in vitro delivery of cefaclor in both simulated intestinal fluid (SIF) without pancreatin (pH 7.4) and simulated gastric fluid (SGF) without pepsin (pH 1.2). Results obtained indicated that the microspheres formulated were highly mucoadhesive and that release of cefaclor in both release media was non-Fickian and was much higher and more rapid in SGF than in SIF and from microspheres based on gelatin alone when compared to those based on gelatin-procine mucin admixtures. The mean area under the plasma level versus time curves (AUC) was shown to be dependent on the formulation with values of 172.3 mug.h/ml for the control, 278.5 mug.h/ml for microspheres based on gelatin only and 353.0 mug.h/ml for microspheres formulated with equal parts of gelatin and mucin indicating that the rectal route may provide a therapeutically viable alternative to the oral route for the delivery of cefaclor. Further indications also emerged of a possibility of site-specific delivery of cefaclor to the small intestine through a careful selection of gelatin type and porcine mucin admixtures prior to formulation of the microspheres. On the whole, the inclusion of S-mucin in the composition of the microspheres had an enhancer effect on the release and rectal bioavailability of cefaclor which may be exploited in the design of a rectal delivery system of the drug.

Pharmacokinetic interaction between cefaclor and bromhexine in healthy Chinese volunteers.

OBJECTIVE: To determine the pharmacokinetic interaction between cefaclor and bromhexine in healthy Chinese volunteers. METHODS: Twelve subjects received a cefaclor (CEF) treatment, a bromhexine (BHX) treatment, and a co-treatment of CEF and BHX with a 3 x 3 Latin square design. The wash-out time between periods was 14 days. The plasma and urine drug concentrations of CEF and BHX were detected by HPLC-UV and LC/MS, respectively. RESULTS: All the 12 volunteers completed the study. There were no significant differences in AUC 0-t and Cmax of CEF in logarithm between the single administration group of CEF and the co-administration group of CEF with BHX. Two one sided t-test showed that CEF was bioequivalent in the 2 groups. There were no significant differences in tmax, MRT, t1/2, and Clr between the 2 groups. Vd/F was significantly lower in the single CEF group than in the co-administration group of CEF and BHX. There were no significant differences of AUC 0-t and Cmax of BHX in logarithm between the single administration group of BHX and the co-administration group of BHX with CEF. Two one sided t-test showed that BHX was bioequivalent in the 2 groups. There were no significant differences in tmax, MRT, t1/2, Vd/F, and Clr between the 2 groups. CONCLUSION: There is no significant pharmacokinetic parameter change in the drug absorption, metabolism, and excretion, but Vd/F of CEF significant increases in the co-administration of CEF with BHX. The co-administration of CEF and BHX has no adverse drug interaction. The increase of Vd/F may be a favorable drug interaction, which may be the mechanism of the synergistic effect of the 2 drugs.

Comparative target site pharmacokinetics of immediate- and modified-release formulations of cefaclor in humans.

Optimal dosing of beta-lactam antibiotics aims at maximizing the time at which drug levels in the interstitial space fluid (ISF)--the fluid that surrounds the causative microorganisms at the target site--exceed the minimal inhibitory concentration (MIC). One potentially attractive strategy to achieve this goal is to administer antibiotics as oral sustained-release formulations. The present study was designed to test the hypothesis that sustained-release formulations could lead to a more suitable pharmacokinetic profile in the ISF at the relevant target site. For this purpose, time versus cefaclor concentration profiles attained in the ISF were measured following administration of two formulations, an immediate- (500 mg IR) and a modified-release formulation in two different doses (500 mg MR and 750 mgMR) in a three-way crossover study of healthy male volunteers (n = 12). For the measurement of unbound cefaclor concentrations in the ISF of human skeletal muscle, the in vivo microdialysis technique was employed. For all three formulations, unbound cefaclor concentration in the ISF closely followed individual plasma concentration profiles in a dose-dependent pattern, with ISF to unbound plasma ratios ranging from 0.67 to 0.73. The mean residence time was found to be significantly longer for the MR formulations versus the IR formulation. The data of the present study indicate that time above MIC values at the target site can be substantially prolonged if an antibiotic is administered as a sustained-release product.

Cefaclor revisited.

OBJECTIVE: This paper describes the rationale for choosing cefaclor for the management of respiratory tract infections. BACKGROUND: Since 1979, cefaclor has established a record of efficacy in the management of respiratory tract infections. Factors contributing to the efficacy and tolerability of this drug include its molecular stability, activity against the most prevalent gram-positive and gram-negative respiratory tract pathogens, rapid absorption, >90% bioavailability, and good penetration into respiratory mucosa. After 2 decades of widespread use, this agent remains clinically effective in patients with respiratory tract infections, making it competitive with other cephalosporins and with macrolides and fluoroquinolones, including many newer agents used for respiratory tract infections. Cefaclor extended-release tablets, the newest formulation, retain the positive efficacy and tolerability attributes of immediate-release cefaclor, varying mainly in the rate of dissolution. The approved indications for extended-release cefaclor include bacterial bronchitis, pharyngitis, and skin infections. METHODS: A MEDLINE search showed that the few adverse effects related to therapy with cefaclor are usually minor and transient and that drug-drug interactions involving cefaclor are rare. CONCLUSIONS: Multiple clinical trials have shown that extended-release cefaclor in 375-mg and 500-mg doses BID demonstrates tolerability and efficacy comparable to those of immediate-release cefaclor 250 mg TID. Extended-release cefaclor is indicated for BID dosing, which should encourage greater compliance.

PK-PD modelling of the effect of cefaclor on four different bacterial strains.

The effect of cefaclor against relevant bacterial strains was studied by employing a combined in vivo pharmacokinetic (PK)-in vitro pharmacodynamic (PD) approach. For this purpose selected isolates of Escherichia coli, Moraxella catarrhalis, Haemophilus influenzae and Streptococcus pneumoniae were exposed in vitro to the interstitial cefaclor profile obtained in vivo in the interstitial space fluid of human tissue after administration of commonly used doses of cefaclor and the change in the number of colony forming units per millilitre (CFU/ml) versus time was monitored. Fitting of the data using a modified E(max)-model resulted in a set of mean pharmacodynamic parameters (k0, k(max), EC50) for each bacterial strain. The parameters derived from these experiments were used in a computer-simulation of the antibacterial effects for different dosing regimens and formulations of cefaclor, notably an immediate (IR) and a modified (MR) release formulation. Dosage regimens were compared using the ratio between the number of bacteria remaining after 24 h of a given treatment (N24h). The results indicate that the number of bacteria of all investigated strains killed per day is equivalent when the same daily dose is administered twice a day with the MR dosage form than when given three times a day with the IR dosage form, in spite of the fact that the MR dosage form has approximately 20% lower bioavailability. Best results were obtained with the three-times a day regimen of the MR formulation. In conclusion, the present in vivo-PK/in vitro-PD simulations of the antimicrobial effects of cefaclor indicate that a twice-daily treatment with a MR formulation may offer a convenient and safe alternative to the conventional tid treatment.

Comparative pharmacokinetics of oral ceftibuten, cefixime, cefaclor, and cefuroxime axetil in healthy volunteers.

STUDY OBJECTIVE: To compare the pharmacokinetics of ceftibuten, cefixime, ceturoxime axetil, and cefaclor after oral administration. DESIGN: Randomized, four-period, crossover study. SETTING: Hospital-based clinical research center. SUBJECTS: Healthy adult men and women volunteers. INTERVENTIONS: Single 400-mg doses of cefixime and ceftibuten, and 500-mg doses of cefuroxime axetil and cefaclor. MEASUREMENTS AND MAIN RESULTS: Serum concentrations were determined by high-performance liquid chromatography methods. The mean oral clearances of cefixime, cefuroxime axetil, and cefaclor were similar, ranging from 20.4-27.0 L/hour; clearance of ceftibuten was approximately 4-fold less, 5.45 L/hour. The serum half-lives of ceftibuten (2.35 hrs) and cefixime (2.38 hrs) were prolonged compared with those of cefuroxime axetil (1.30 hrs) and cefaclor (0.693 hr). These agents also differed in terms of time to maximum concentration, time to peak plasma level, area under the curve, and apparent volume of distribution, the last reflecting differences in biovailability. CONCLUSION: Ceftibuten had a relatively high time to maximum concentration and long half-life, resulting in a 3.5-fold higher area under the curve than cefixime, cefuroxime axetil, and cefaclor. These pharmacokinetic data can be used as a basis to compare the four oral cephalosporins; however, comparative susceptibility data must also be considered.

Pharmacokinetic profile of cefaclor.

Cefaclor is a well-absorbed oral cephalosporin antibiotic. Peak concentrations in serum are attained within 30-60 minutes. Food intake reduces the rate, but not the extent of absorption. Cefaclor is not metabolized to a significant degree, but it degrades chemically in the body with an approximate half-life of 2 hours. Most of the drug is excreted unchanged in the urine, the serum half-life after oral administration is 0.5-0.7 hours. Due to the chemical degradation, cefaclor does not accumulate to the same degree as other cephalosporins in case of renal impairment.

Pharmacokinetic study of cefaclor in chronic maxillary sinusitis.

The pharmacokinetics of the maxillary sinus fluid were studied in 42 patients (26 males and 16 females), suffering from chronic maxillary sinusitis, after oral administration of 0.5g or 1g cefaclor. A thin plastic catheter, for sinus secretion sampling, was inserted in the sinus cavity and remained in place throughout the study. Sinus fluid levels of cefaclor (0.5g), measured by agar and well-diffusion microbiological method, ranged between 0.17-0.19, 0.28-0.42, 0.18-0.22 and 0.12-0.16 microgram/ml at 2, 4, 6 and 8 hour intervals respectively. Levels ranging between 0.15-0.26, 0.37-0.90, 0.23-0.27 and 0.16-0.19 microgram/ml were found after the administration of 1g cefaclor at the same time intervals respectively. Higher levels were found in purulent nasal material than in cystic fluid aspirates.

New insight into the clinical pharmacokinetics of cefaclor: tissue penetration.

The serum pharmacokinetic data presented are generally in agreement with those obtained by other authors with both the cefaclor IR (immediate release) and AF (advanced formulation) or MR (modified release) formulations. With the new sustained-release formulation, the time of peak (Tmax) and mean residence time (MRT) values are significantly longer than those observed with the standard cefaclor IR. For the first time the penetration of the MR formulation of cefaclor was determined both in suction blister fluid (SBF) and alveolar epithelial lining fluid (ELF). Cefaclor demonstrated a high tissue distribution, with a high penetration index (PI) into blister fluid, which is at least representative of a relatively large volume of fluid-filled spaces and in part of highly vascularized tissues. SBF and ELF concentrations were higher than blood levels starting at the 4th-6th hour after dose, with longer elimination half-lives from the extravascular compartment than from serum. Cefaclor has a favorable pharmacokinetic profile, especially the new sustained-release formulation, which maintains effective concentrations for a longer time than the IR preparation. The MR formulation improves the kinetic properties of the cefaclor molecule with a prolonged MRT which allows a daily dosage of 750 mg every 12 h.

Cefaclor into the millennium.

We review the discovery and development of the cephalosporins and subsequently cefaclor. Cefaclor is active against a wide range of commonly encountered bacterial pathogens, acting by inhibiting cell wall synthesis. Its in vitro activity compares favourably with other beta-lactam antibiotics. Its pharmacokinetic properties indicate that an 8-hourly dosing schedule is appropriate. In addition a delayed release formulation allowing twice daily dosage has been developed. The efficacy of both formulations of cefaclor has been verified by many clinical trials. Cefaclor has been widely used in infections of the respiratory tract (including otitis media), urinary tract and soft tissues. The results of therapy are summarized. The low incidence of adverse events is highlighted and the beneficial influence of this on compliance is described. Finally, the pharmaco-economics of cefaclor are considered.

Interrelationship between the pharmacokinetics and pharmacodynamics of cefaclor advanced formulation in patients with acute exacerbation of chronic bronchitis.

Cefaclor advanced formulation (cefaclor AF) is an extended-release form of the oral cephalosporin cefaclor. When cefaclor AF 750 mg twice-daily and cefaclor immediate release 500 mg three-times-a-day are compared there is a skew to the right of the pharmacokinetic profile and higher levels are achieved. Based on this pharmacokinetic finding, we examined the relationship between the bacterial susceptibility to cefaclor (MIC), the achieved cefaclor AF serum and sputum concentrations, and in vivo eradication of the bacteria in 36 patients with acute exacerbations of chronic bronchitis. The mean peak concentrations in serum and sputum 5 h after administration were 8.6 microg/ml (95% CI: 8.1 microg/ml - 9.1 microg/ml) and 1.5 microg/ml (95% CI: 1.4 microg/ml - 1.7 microg/ml), respectively. Cefaclor was always detectable 8 h after administration. At post therapy, treatment was successful in 31 (86.1%) patients. Cefaclor concentrations in serum persisted above the MIC for more than 40% of dosing interval in 31 subjects, and those in sputum in 24 patients. Treatment was successful in all subjects with percent of time above the MIC in serum of >40%, whereas the time that levels in sputum stayed above the MIC was not the pharmacodynamic parameter that correlated best with therapeutic efficacy for cefaclor. Our data demonstrate that when cefaclor AF is dosed twice-daily, the in vivo pharmacodynamic susceptibility breakpoint is 8 microg/ml. The good activity and pharmacokinetics of cefaclor AF provide serum concentrations higher than the MIC of Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis for more than 40% of the validated dosing interval. Therefore, it might be considered for first choice treatment of acute exacerbations of chronic bronchitis.

Clinical pharmacokinetics of five oral cephalosporins in calves.

The minimal inhibitory concentrations (MIC) of cephalexin, cephradine, cefaclor, cefatrizine and cefadroxil for Salmonella species, Escherichia coli and Pasteurella multocida isolated previously from young calves were determined. The MIC90 values for cephalexin, cephradine and cefadroxil ranged between 3.12 micrograms ml-1 and 12.5 micrograms ml-1, whereas those of cefatrizine and cefaclor were 3.12 micrograms ml-1 and 0.78 microgram ml-1, respectively. Each drug was administered intravenously and orally to groups of pre-ruminating calves and orally to early ruminating calves. Although the pharmacokinetic characteristics of the drugs after intravenous injection were similar to other beta-lactam antibiotics, significant differences between the cephalosporins examined were found in respect of certain kinetic parameters. The drugs showed rapid absorption into the systemic circulation after oral administration to pre-ruminating calves but the elimination half-life values (t1/2 beta) varied between three hours (cefaclor and cefadroxil) and nine hours (cefatrizine). The bioavailability of the drugs was about 35 per cent of the administered dose. Co-administration of probenecid with each antibiotic caused a twofold or greater increase in peak serum drug concentrations (Cmax) but the effect on t1/2 beta was variable. Cephalexin, cephradine and cefaclor given to the ruminating calves resulted in very low serum or plasma concentrations and their use should be restricted to younger calves. Cefadroxil was found to give the highest serum concentrations in this age group but had significantly lower bioavailability when compared with the unweaned calves. Provisional oral dosage regimens were computed for each cephalosporin on the basis of the MIC data and the kinetic parameters derived from intravenous and oral drug administration.

The effect of four different types of food on the bioavailability of cefaclor.

This randomized, open-label, balanced, five-treatment, five-period, five-sequence, single-dose and crossover pharmacokinetic study assessed the effect of different types of food on the bioavailability of cefaclor in 18 healthy male volunteers. A single dose of cefaclor, 250-mg capsule was administered at five occasions: after overnight fasting, after two vegetarian (high-fat and low-fat) diets and two non-vegetarian (high-fat and low-fat) diets. Serial blood samples were collected upto 8 h post dose. Serum cefaclor concentrations were determined by a validated HPLC method. AUC values were not significantly affected by food intake, but the T(max) was prolonged and C(max) was decreased, depending on the type of meal. The non-vegetarian diets affected the rate of absorption of cefaclor more than the vegetarian diets. The least decrease in C(max) was produced by low-fat vegetarian diet, while the maximum decrease was produced by high-fat non-vegetarian diet. The results of this study indicate that while the rate of absorption of cefaclor is significantly decreased, the extent of absorption and the rate of elimination are not significantly decreased in the presence of food. As compared to high-fat non-vegetarian diet, the time above MIC50 concentration was significantly increased by low-fat vegetarian diet. The implications of these findings for the large vegetarian Indian population are considerable.

Comparative effect of different types of food on the bioavailability of cefaclor extended release tablet.

This randomized, six-treatment, six-period, six sequence, single dose, crossover pharmacokinetic study assessed the effect of different types of food on the bioavailability of 500-mg cefaclor extended release tablet in 23 healthy male volunteers. A single dose of cefaclor extended release 500-mg tablet was administered at six occasions: after overnight fasting, after two vegetarian (high-fat and low-fat), two non-vegetarian (high-fat and low-fat) and rice diets. Serial blood samples were collected up to 12 h after dose. Serum cefaclor concentrations were determined by a validated HPLC method. An almost equivalent increase in both Cmax and AUC was observed with both high-fat non-vegetarian and low-fat vegetarian breakfasts. However, when MIC90 values, a pharmacodynamic end-point were compared, the low-fat vegetarian diet fared better than the high-fat non-vegetarian diet. The results obtained favor low-fat vegetarian diet (breakfast) to be taken with cefaclor extended release tablet to achieve maximum benefit in terms of clinical efficacy.

[Comparison of pharmacokinetics/pharmacodynamics of cefdinir, cefpodoxime proxetil and cefaclor against common bacteria of community acquired infections].

OBJECTIVE: To compare the pharmacokinetics/pharmacodynamics property of cefdinir, cefpodoxime proxetil and cefaclor against common bacteria of community acquired infections and evaluate the recommended regimens. METHODS: The antibacterial activities of 3 agents against 238 clinical isolates were determined by standard agar dilution test and the pharmacokinetics of these antibiotics in male healthy volunteers were conducted in Latin-square manner. The time over MIC (T > MIC) of serum antibiotic concentrations were calculated with pharmacokinetic equation and MIC. RESULTS: The value of MIC90 s cefdinir against these bacterial strains except penicillin non-sensitive pneumococci were 0.031-1 mg/L. Cefpodoxime held similar antibacterial activity with cefdinir, but was less potent against staphylococci. Cefaclor had much higher MIC values than other two drugs. After oral administration of 250 mg cefaclor, the drug concentration quickly reached peak concentration of 4.95 mg/L +/- 2.41 mg/L and the eliminative half time was 0.69 h +/- 0.6 h; the Tmax, Cmax and T1/2beta of cefdinir and cefpodoxime after oral administration of 100 mg were 2.5 h +/- 0.48 h, 0.81 mg/L +/- 0.19 mg/L, 1.73 h +/- 0.3 h and 2.38 h +/- 0.43 h, 1.12 mg/L +/- 0.28 mg/L, 1.92 h +/- 0.55 h, respectively. T > MIC of cefdinir in thrice daily administration were longer than 40% of medication interval against most of the tested isolates; no T > MIC period was found in cefpodoxime against staphylococci and the T > MICs of cefaclor after 250 mg oral administration were shorter than expected values against most bacteria. CONCLUSION: With powerful antibacterial activity, the T > MICs of cefdinir after 100 mg oral administration can meet with the clinical requirement in most infections; PK/PD value of cefpodoxime proxetil against staphylococci is lower than expectancy and 250 mg cefaclor 3 times daily is not enough to the treatment of common community acquired infections, the regimens of cefpodoxime proxetil and cefclor should be furtherly optimized.

Determination of cefaclor by UPLC-MS-MS for a Chinese pharmacokinetic study.

A novel method has been developed for the determination of cefaclor in human plasma by ultra-performance liquid chromatography combined with tandem mass spectrometry (UPLC-MS-MS). The plasma was treated by a single step of protein precipitation with acetonitrile. The chromatographic separation was performed on a Waters Acquity UPLC BEH C18 (2.1 × 100 mm, 1.7 µm) with a gradient mobile phase consisting of 0.1% formic acid and acetonitrile at a flow rate of 0.4 mL/min. The analyses were conducted by multiple reaction monitoring using the precursor-to-product combinations of m/z 367.5 → 173.8 (cefaclor) and m/z 454.1 → 160.3 (internal standard). Validation results indicated that the lower limit of quantification was 2 ng/mL and the assay exhibited a linear range of 2-10,000 ng/mL. Quality control samples (5, 200 and 5,000 ng/mL) in five replicates from three different runs of analysis demonstrated an intra-assay precision (relative standard deviation) of 3.7-10.7%, an inter-assay precision of 5.8-8.9%, and an overall accuracy of < 15%. A sensitive and specific method for quantifying cefaclor in human plasma has been devised and successfully applied to a pharmacokinetic study.

Drug interaction studies reveal that simotinib upregulates intestinal absorption by increasing the paracellular permeability of intestinal epithelial cells.

HYPOTHESIS: Simotinib hydrochloride (SIM6802), which is a new epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), is often prescribed for cancer patients with comorbidities and has serious adverse effects on gastrointestinal physiology. The drug-drug interactions (DDIs) between simotinib and other drugs in combination and the underlying mechanism of its gastrointestinal toxicity remain unclear. We hypothesized that the DDIs and the gastrointestinal toxicity of simotinib were related to its effects on the permeability of the intestine. METHODS: To determine the intestinal absorption capacity, pharmacokinetic studies and an in situ loop assay were used. The intestinal permeability was measured by a Caco-2 Transwell model. Real time PCR and Western blots were applied to detecting the expression changes of cell junction genes. RESULTS: Our research demonstrated that simotinib upregulated the absorption of cefaclor, valaciclovir and acyclovir. The increase of non-selective absorption was caused by the low expression of cell junction gene afadin-6 and the increase in paracellular permeability in intestinal epithelial cells after simotinib treatment. CONCLUSION: These findings revealed that simotinib upregulated intestinal absorption by increasing the paracellular permeability of intestinal epithelial cells. Our research provides theoretical bases for better formulation of EGFR-TKIs to alleviate adverse gastrointestinal effects and also provides guidance for clinical administration of simotinib.