Edoxaban drug-drug interactions with ketoconazole, erythromycin, and cyclosporine.

AIMS: Edoxaban, a novel factor Xa inhibitor, is a substrate of cytochrome P450 3 A4 (CYP3A4) and the efflux transporter P-glycoprotein (P-gp). Three edoxaban drug-drug interaction studies examined the effects of P-gp inhibitors with varying degrees of CYP3A4 inhibition. METHODS: In each study, healthy subjects received a single oral dose of 60 mg edoxaban with or without an oral dual P-gp/CYP3A4 inhibitor as follows: ketoconazole 400 mg once daily for 7 days, edoxaban on day 4; erythromycin 500 mg four times daily for 8 days, edoxaban on day 7; or single dose of cyclosporine 500 mg with edoxaban. Serial plasma samples were obtained for pharmacokinetics and pharmacodynamics. Safety was assessed throughout the study. RESULTS: Coadministration of ketoconazole, erythromycin, or cyclosporine increased edoxaban total exposure by 87%, 85%, and 73%, respectively, and the peak concentration by 89%, 68%, and 74%, respectively, compared with edoxaban alone. The half-life did not change appreciably. Exposure of M4, the major active edoxaban metabolite, was consistent when edoxaban was administered alone or with ketoconazole and erythromycin. With cyclosporine, M4 total exposure increased by 6.9-fold and peak exposure by 8.7-fold, suggesting an additional interaction. Pharmacodynamic effects were reflective of increased edoxaban exposure. No clinically significant adverse events were observed. CONCLUSIONS: Administration of dual inhibitors of P-gp and CYP3A4 increased edoxaban exposure by less than two-fold. This effect appears to be primarily due to inhibition of P-gp. The impact of CYP3A4 inhibition appears to be less pronounced, and its contribution to total clearance appears limited in healthy subjects.

Preparation and characterization of macroporous monoliths imprinted with erythromycin.

The synthesis of macroporous molecularly imprinted monoliths was performed using the monomers system 2-hydroxyethyl methacrylate-ethylene glycol dimethacrylate and erythromycin as a template. The copolymerization was carried out in situ inside 50 mm × 4.6 mm i.d. stainless-steel tubing. The morphology of the monoliths was examined with scanning electron microscopy. The porous characteristics were determined both from the data of hydrodynamic permeability of monoliths and by means of mercury intrusion porosimetry. The retention parameters of target substance (erythromycin), values of calculated imprinting factors and apparent dynamic dissociation constants were obtained for monoliths prepared with the application of different amount of template (4, 8 and 12 mol%). The separations of the mixtures azithromycin/erythromycin and ciprofloxacin/erythromycin were demonstrated. Additionally, the possibility of erythromycin quantification in human blood plasma was shown.

[Evaluation of erythromycin concentration in the umbilical artery serum]. / Ocena stezenia erytromycyny w surowicy krwi z tetnicy pepowinowej.

OBJECTIVES: The aim of the study was to investigate the effectiveness of erythromycin in preventing intrauterine infection caused by group B streptococcus (GBS). MATERIAL AND METHODS: The study included 20 pregnant women with GBS-positive screening or whose laboratory screening was not available, who delivered between April 17, 2013 and July 22, 2013. The women were given 600 mg of erythromycin intravenously After delivery blood was drawn in parallel from maternal antecubital vein and umbilical cord artery Serum erythromycin concentrations were evaluated using enzyme-linked immunosorbent assay (ELISA) kit. Statistical analysis for measurable and non-measurable characteristics were performed, correlation coefficients for each pair of variables were calculated in order to investigate the sought dependence. RESULTS: Mean placental transfer of erythromycin was 2.04%. There was a high correlation between umbilical artery serum and maternal serum erythromycin concentration. Selected variables of mothers in the control group had no effect on serum erythromycin concentration in the umbilical artery CONCLUSIONS: Transplacental transfer of erythromycin is limited (2.04%). Intravenous application of erythromycin at a dose of 600 mg does not allow to achieve the value of MIC50 and MIC90 for erythromycin against strains S. agalactiae in umbilical artery serum, what suggests a compromised efficacy in the treatment of intrauterine fetal infections. At the same time, the placenta seems to be an effective barrier reducing fetal exposure when this macrolide is used to treat maternal infections.

Effect of netupitant, a highly selective NK1 receptor antagonist, on the pharmacokinetics of midazolam, erythromycin, and dexamethasone.

PURPOSE: Netupitant is a new highly selective neurokinin-1 receptor antagonist being studied for the prevention of nausea and vomiting in patients undergoing chemotherapy. In vitro studies suggest that netupitant inhibits the cytochrome P-450 isoenzyme 3A4 (CYP3A4). Because netupitant may be used with a variety of drugs, which may be substrates of CYP3A4, two studies were designed to establish the potential risk for drug-drug interaction with three different CYP3A4 substrates: midazolam, erythromycin, and dexamethasone. METHODS: Both trials were three-period crossover studies performed in healthy subjects. In the first study, 20 subjects received netupitant and either midazolam or erythromycin. In the second study, 25 subjects received netupitant and dexamethasone. Serial blood samples were collected over the course of the two studies and pharmacokinetic parameters were determined for all analytes. RESULTS: Netupitant, by inhibiting the CYP3A4, increased the C max and AUCinf of midazolam by 40 and 144 %, respectively, and the C max and AUCinf of erythromycin by 30 %. Netupitant was shown to increase the exposure to dexamethasone in a dose-dependent manner with the mean increase in AUC and C max by 72 and 11 %, respectively, on day 1 and by 138 and 75 %, respectively, on day 4 when co-administered with 300 mg of netupitant. CONCLUSIONS: The results of these studies suggest that netupitant is a moderate inhibitor of CYP3A4 and therefore, co-administration with drugs that are substrates of CYP3A4 may require dose adjustments. Treatments were well tolerated in both studies.

Pharmacokinetics and residue depletion of erythromycin in rainbow trout Oncorhynchus mykiss (Walbaum).

Erythromycin (ERY) is a drug active against Gram-positive bacteria such as Lactococcus garvieae, a pathogen responsible for an important disease that may cause a substantial decrease in rainbow trout Oncorhynchus mykiss (Walbaum) production, the species of fish most commonly produced in Italy. In the literature, studies on the kinetics behaviour of ERY in fish are limited. Therefore, the aim of the present study was to evaluate the pharmacokinetics of ERY in rainbow trout after a single oral treatment with 75 mg kg⁻¹ body weight (b.w.) of ERY and the residue depletion after multiple oral administration of 75 mg kg⁻¹ b.w. day⁻¹ of ERY for 10 days. Blood concentrations of ERY increased up to 20.24 ± 13.32 µg mL⁻¹ at 6 h, then decreased to 5.97 ± 3.89 µg mL⁻¹ at 24 h. The time during which the antibiotic remains in the bloodstream at concentrations exceeding the MIC (T > MIC) and the area under the serum concentration-time curve (AUC)/MIC are both pharmacokinetic-pharmacodynamic (PK/PD) predictors of ERY efficacy, and the data obtained allowed us to hypothesize that a dosage of 75 mg kg⁻¹ b.w. day⁻¹ of ERY could treat the lactococcosis in trout. Regarding the study of ERY depletion, rapid elimination was observed in tissue (muscle plus adherent skin); in fact the concentrations were below the limit of quantification in all samples (except two) by day 10 post-treatment. ERY is not licensed in Europe for use in aquaculture, and its use is possible only by off-label prescription with a precautionary withdrawal time of 500 degree-days, as established by Directive 2004/28/EC. From the data obtained in this study, a withdrawal time of 8.90 days was calculated, corresponding, in our experimental conditions, to 117.5 degree-days, a value significantly lower than that established by the European directive.

Blood, tissue, and intracellular concentrations of erythromycin and its metabolite anhydroerythromycin during and after therapy.

For macrolides, clinical activity but also the development of bacterial resistance has been attributed to prolonged therapeutic and subtherapeutic concentrations. Although erythromycin is a long-established antimicrobial, concomitant determination of the pharmacokinetics of erythromycin and its metabolites in different compartments is limited. To better characterize the pharmacokinetics of erythromycin and its anhydrometabolite (anhydroerythromycin [AHE]) in different compartments during and after the end of treatment with 500 mg of erythromycin four times daily, concentration-time profiles were determined in plasma, interstitial space of muscle and subcutaneous adipose tissue, and white blood cells (WBCs) at days 1 and 3 of treatment and 2 and 7 days after end of therapy. In WBCs, concentrations of erythromycin exceeded those in plasma approximately 40-fold, while free concentrations in plasma and tissue were comparable. The observed delay of peak concentrations in tissue might be caused by fast initial cellular uptake. Two days after the end of treatment, subinhibitory concentrations were observed in plasma and interstitial space of both soft tissues, while 7 days after the end of treatment, erythromycin was not detectable in any compartment. This relatively short period of subinhibitory concentrations may be advantageous compared to other macrolides. The ratio of erythromycin over AHE on day 1 was highest in plasma (2.81 ± 3.45) and lowest in WBCs (0.27 ± 0.22). While the ratio remained constant between single dose and steady state, after the end of treatment the concentration of AHE declined more slowly than that of the parent compound, indicating the importance of the metabolite for the prolonged drug interaction of erythromycin.

Plasma erythromycin concentrations predict feeding outcomes in critically ill patients with feed intolerance.

OBJECTIVE: Motilin receptors are rapidly down-regulated by exposure to erythromycin, and its progressive loss of clinical prokinetic effect may relate to higher plasma drug concentrations. This study aimed to evaluate the relationship between plasma erythromycin concentrations and feeding outcomes in critically ill patients. DESIGN: Observational comparative study. SETTING: Tertiary critical care unit. PATIENTS: Twenty-nine feed-intolerant (gastric residual volume >250 mL) mechanically ventilated, medical critically ill patients. INTERVENTIONS: Patients received intravenous erythromycin 200 mg twice daily for feed intolerance. MEASUREMENTS: Plasma erythromycin concentrations were measured 1 and 7 hrs after drug administration on day 1. Success of enteral feeding, defined as 6-hourly gastric residual volume of ≤ 250 mL with a feeding rate ≥ 40 mL/h, was recorded over 7 days. RESULTS: At day 7, 38% (11 of 29) of patients were feed tolerant. Age, Acute Physiology and Chronic Health Evaluation scores, serum glucose concentrations, and creatinine clearance were comparable between successful and failed feeders. Both plasma erythromycin concentrations at 1 and 7 hrs after drug administration were significantly lower in successfully treated patients compared to treatment failures (1 hr: 3.7 ± 0.8 mg/L vs. 7.0 ± 1.0 mg/L, p = .02; and 7 hr: 0.7 ± 0.3 mg/L vs. 2.8 ± 0.6 mg/L, p = .01). There was a negative correlation between the number of days to failure of feeding and both the 1-hr (r = -.47, p = .049) and 7-hr (r = -.47, p = .050) plasma erythromycin concentrations. A 1-hr plasma concentration of >4.6 mg/L had 72% sensitivity and 72% specificity, and a 7-hr concentration of ≥ 0.5 mg/L had 83% sensitivity and 72% specificity in predicting loss of response to erythromycin. CONCLUSIONS: In critically ill feed-intolerant patients, there is an inverse relationship between plasma erythromycin concentrations and the time to loss of clinical motor effect. This suggests that erythromycin binding to motilin receptors contributes to variations in the duration of prokinetic response. The use of lower doses of erythromycin and tailoring the dose of erythromycin according to plasma concentrations may be useful strategies to reduce erythromycin tachyphylaxis.

Maternal-amniotic-fetal distribution of macrolide antibiotics following intravenous, intramuscular, and intraamniotic administration in late pregnant sheep.

OBJECTIVE: The objective of the study was to explore the maternal-fetal pharmacokinetics of intraamniotic (IA), intravenous (IV), or intramuscular (IM) administration of erythromycin or azithromycin in a pregnant sheep model. STUDY DESIGN: Pregnant ewes of 115-121 days' gestation received a single maternal IV infusion (5 mg/kg over 60 min), a single IM injection, or a single IA injection (3.2 mg/kg fetal weight) of either erythromycin lactobionate or azithromycin. Maternal/fetal blood and amniotic fluid (AF) samples were collected across 48 h for macrolide assay by liquid chromatography and tandem mass spectrometry. RESULTS: Maternal administration achieved therapeutic maternal plasma macrolide concentrations (≥0.5 µg/mL) with low concentrations in AF equivalent to less than 7% transfer; fetal plasma levels were even lower (<1.5% transfer). The IA administration achieved therapeutic concentrations in AF and sustained for 48 h, with poor maternal-fetal transfer (<1% maternal, <0.3% fetal). Modest pharmacokinetic differences were evident between erythromycin and azithromycin. CONCLUSION: Maternal macrolide administration achieves subtherapeutic concentrations in AF or fetal plasma, whereas a single IA injection achieves therapeutic concentrations in AF but not in maternal-fetal circulations. Combined maternal and single IA administration of macrolides may be a more effective regimen for treatment of intrauterine, but not fetal, infection.

VIP differentially activates beta2 integrins, CR1, and matrix metalloproteinase-9 in human monocytes through cAMP/PKA, EPAC, and PI-3K signaling pathways via VIP receptor type 1 and FPRL1.

The neuropeptide vasoactive intestinal peptide (VIP) regulates the exocytosis of secretory granules in a wide variety of cells of neuronal and non-neuronal origin. In human monocytes, we show that the proinflammatory effects of VIP are associated with stimulation of exocytosis of secretory vesicles as well as tertiary (gelatinase) granules with, respectively, up-regulation of the membrane expression of the beta2 integrin CD11b, the complement receptor 1 (CD35), and the matrix metalloproteinase-9 (MMP-9). Using the low-affinity formyl peptide receptor-like 1 (FPRL1) antagonist Trp-Arg-Trp-Trp-Trp-Trp (WRW4) and the exchange protein directly activated by cAMP (EPAC)-specific compound 8CPT-2Me-cAMP and measuring the expression of Rap1 GTPase-activating protein as an indicator of EPAC activation, we found that the proinflammatory effect of VIP is mediated via the specific G protein-coupled receptor VIP/pituitary adenylate cyclase-activating protein (VPAC1) receptor as well as via FPRL1: VIP/VPAC1 interaction is associated with a cAMP increase and activation of a cAMP/p38 MAPK pathway, which regulates MMP-9, CD35, and CD11b exocytosis, and a cAMP/EPAC/PI-3K/ERK pathway, which regulates CD11b expression; VIP/FPRL1 interaction results in cAMP-independent PI-3K/ERK activation with downstream integrin up-regulation. In FPRL1-transfected Chinese hamster ovary-K1 cells lacking VPAC1, VIP exposure also resulted in PI-3K/ERK activation. Thus, the proinflammatory effects of VIP lie behind different receptor interactions and multiple signaling pathways, including cAMP/protein kinase A, cAMP/EPAC-dependent pathways, as well as a cAMP-independent pathway, which differentially regulates p38 and ERK MAPK and exocytosis of secretory vesicles and granules.

Quantitative determination of erythromycylamine in human plasma by liquid chromatography-mass spectrometry and its application in a bioequivalence study of dirithromycin.

A sensitive, rapid liquid chromatographic-electrospray ionization mass spectrometric method for determination of erythromycylamine in human plasma was developed and validated. Erythromycylamine in plasma (0.2 mL) was extracted with ethyl acetate, the organic phase was transferred to another clear 1.5 mL Eppendorf tube and evaporated to dryness under gentle nitrogen stream at 45 degrees C, and the residue was dissolved in 100 microL of mobile phase. The samples were separated using a Thermo Hypersil HyPURITY C18 reversed-phase column (150 mm x 2.1 mm I.D., 5 microm). A mobile phase containing 10 mM of ammonium acetate (pH = 6.4)-acetonitrile-methanol (50:10:40, v/v/v) was used isocratically eluting at a flow rate of 0.2 mL/min. Erythromycylamine and its internal standard (IS), midecamycin, were measured by electrospray ion source in positive selective ion monitoring mode. The method demonstrated that good linearity ranged from 4.5 to 720 ng/mL with r = 0.9997. The limit of quantification for erythromycylamine in plasma was 4.5 ng/mL with good accuracy and precision. The mean extraction recovery of the method was higher than 75.1% and 72.7% for erythromycylamine and IS, respectively. The intra-day and inter-day precision ranged from 5.2% to 6.4% and 5.6-9.3% (relative standard deviation, RSD), respectively. The established method has been successfully applied to a bioequivalence study of two dirithromycin formulations for 18 healthy volunteers.

Chemotherapy of experimental streptococcal endocarditis. I. Comparison of commonly recommended prophylactic regimens.

The effectiveness of various antibiotics commonly recommended for the prophylaxis of bacterial endocarditis has been evaluated in experimental streptococcal endocarditis in rabbits. High doses of penicillin G did not prevent the development of this infection. The only consistently successful prophylactic regimens using penicillin alone were those which provided for both an early high serum level and more than 9 h of effective antimicrobial action. Vancomycin was the only other drug which proved uniformly successful when given alone, even though the duration of its antimicrobial action in the blood was only 3 h. However, combined therapy using penicillin G or ampicillin with streptomycin was always effective in prophylaxis. Treatment with single injections of ampicillin, cephaloridine, cephalexin, clindamycin, cotrimoxazole, rifampicin, streptomycin, erythromycin, and tetracycline failed to prevent infection. The findings provide information on the effect of antimicrobials in vivo and may be applicable to the chemoprophylaxis of infective endocarditis in clinical practice.

Quantitative determination of tilmicosin in canine serum by high performance liquid chromatography-tandem mass spectrometry.

A highly sensitive and quantitative LC/MS/MS assay for the determination of tilmicosin in serum has been developed and validated. For sample preparation, 0.2 mL of canine serum was extracted with 3 mL of methyl tert-butyl ether. The organic layer was transferred to a new vessel and dried under nitrogen. The sample was then reconstituted for analysis by high performance liquid chromatography-tandem mass spectrometry. A Phenomenex Luna C8(2) analytical column was used for the chromatographic separation. The eluent was subsequently introduced to the mass spectrometer by electrospray ionization. A single range was validated for 50-5000 ng/mL for support of toxicokinetic studies. The inter-day relative error (inaccuracy) for the LLOQ samples ranged from -5.5% to 0.3%. The inter-day relative standard deviations (imprecision) at the respective LLOQ levels were < or =10.1%.

Determination of erythromycin in rat plasma with capillary electrophoresis-electrochemiluminescence detection of tris(2,2'-bipyridyl) ruthenium(II).

A fast and sensitive approach for determination of erythromycin in rat plasma was described. The method used capillary electrophoresis coupled with end-column electrochemiluminescence (ECL) detection of Ru(bpy)(3)(2+). The separation column used had an inner diameter of 75 microm. The running buffer was 15 mmol/L sodium phosphate (pH=7.5). The solution in the detection cell was 50 mmol/L sodium phosphate (pH=8.0) and 5 mmol/L Ru(bpy)(3)(2+). ECL intensity varied linearly with erythromycin concentration from 1.0 ng/mL to 10 microg/mL. The detection limit (S/N=3) was 0.35 ng/mL. The relative standard deviations, of ECL intensity and migration time for eight consecutive injections of 1.0 microg/mL erythromycin (n=8), were 1.3% and 1.8%, respectively. The method was successfully applied to erythromycin determination in rat plasma. The recovery ranged from 92.5 to 97.5%.

Hemodynamic and electrophysiological effects of mitemcinal (GM-611), a novel prokinetic agent derived from erythromycin in a halothane-anesthetized canine model.

Mitemcinal (GM-611) is a novel erythromycin-derived prokinetic agent that acts as an agonist at the motilin receptor. We investigated the QT-prolonging effects of mitemcinal using a halothane-anesthetized canine model. Intravenous administration of mitemcinal at doses of more than 8.3 mg/kg per 10 min significantly prolonged the QT interval corrected by Fridericia's corrections. Mitemcinal exhibited a bradycardiac effect and produced significantly greater prolongation in monophasic action potential duration (MAP(90)) at sinus rhythm compared with MAP(90) at pacing and showed reverse use-dependent prolongation of repolarization, suggesting that the negative chronotropic effect of mitemcinal potentiates the prolongation of the repolarization period. A technique using MAP/pacing electrodes allowed measurements of both MAP(90) and effective refractory period (ERP) simultaneously at the same ventricular site. Although mitemcinal slightly prolonged the MAP(90(CL400)) and ERP in comparison with the control group at the dose of 25 mg/kg per 10 min, the terminal repolarization period, the difference between MAP(90(CL400)) and ERP, did not increase suggesting the absence of a proarrhythmic effect even with a 7000-fold for the therapeutic blood concentration as free level. The electrophysiological results from mitemcinal in this study indicate that the risk of serious arrhythmia such as torsades de pointes, a major clinical concern related to QT interval prolongation, might be low.

Preclinical electrophysiology assays of mitemcinal (GM-611), a novel prokinetic agent derived from erythromycin.

Mitemcinal (GM-611) is a novel erythromycin-derived prokinetic agent that acts as an agonist at the motilin receptor. Erythromycin has shown QT prolongation and torsades de pointes (TdP) in humans and cisapride, a second class of prokinetic agents typified by the 5-HT(4) receptor agonist, has been terminated due to TdP. In this study an extended series of safety pharmacology protocols and evaluations have been undertaken to assess the potential risk of mitemcinal on QT prolongation or proarrhythmic effects. Mitemcinal and its metabolites, GM-577 and GM-625, inhibited the human ether-a-go-go-related gene (HERG) tail current in a concentration-dependent manner with IC(50) values of 20.2, 41.7, and 55.0 microM, respectively. Administration of 10 mg/kg mitemcinal in anesthetized guinea pigs resulted in a slight prolongation of the monophasic action potential (MAP) duration during atrial pacing at the plasma concentration of mitemcinal 1.1 microM, with low maximum increases in MAPD(70) (6.6%) and MAPD(90) (4.6%) relative to vehicle. A 10-min infusion of 20 mg/kg of mitemcinal in a proarrhythmic rabbit model did not evoke TdP even when QT and corrected QT (QTc) intervals were significantly prolonged. In this study, the Cmax plasma-free concentration of mitemcinal indicates that the prolongation was more than 400-fold that of the therapeutic dose. Our findings of a wide safety margin and the absence of TdP within this margin suggest that mitemcinal may provide sufficient safety in clinical use.

Use of microdosing to predict pharmacokinetics at the therapeutic dose: experience with 5 drugs.

OBJECTIVES: A volunteer trial was performed to compare the pharmacokinetics of 5 drugs--warfarin, ZK253 (Schering), diazepam, midazolam, and erythromycin--when administered at a microdose or pharmacologic dose. Each compound was chosen to represent a situation in which prediction of pharmacokinetics from either animal or in vitro studies (or both) was or is likely to be problematic. METHODS: In a crossover design volunteers received (1) 1 of the 5 compounds as a microdose labeled with radioactive carbon (carbon 14) (100 microg), (2) the corresponding (14)C-labeled therapeutic dose on a separate occasion, and (3) simultaneous administration of an intravenous (14)C-labeled microdose and an oral therapeutic dose for ZK253, midazolam, and erythromycin. Analysis of (14)C-labeled drugs in plasma was done by use of HPLC followed by accelerator mass spectrometry. Liquid chromatography-tandem mass spectrometry was used to measure plasma concentrations of ZK253, midazolam, and erythromycin at therapeutic concentrations, whereas HPLC-accelerator mass spectrometry was used to measure warfarin and diazepam concentrations. RESULTS: Good concordance between microdose and therapeutic dose pharmacokinetics was observed for diazepam (half-life [t((1/2))] of 45.1 hours, clearance [CL] of 1.38 L/h, and volume of distribution [V] of 90.1 L for 100 microg and t((1/2)) of 35.7 hours, CL of 1.3 L/h, and V of 123 L for 10 mg), midazolam (t((1/2)) of 4.87 hours, CL of 21.2 L/h, V of 145 L, and oral bioavailability [F] of 0.23 for 100 microg and t((1/2)) of 3.31 hours, CL of 20.4 L/h, V of 75 L, and F of 0.22 for 7.5 mg), and development compound ZK253 (F = <1% for both 100 microg and 50 mg). For warfarin, clearance was reasonably well predicted (0.17 L/h for 100 microg and 0.26 L/h for 5 mg), but the discrepancy observed in distribution (67 L for 100 microg and 17.9 L for 5 mg) was probably a result of high-affinity, low-capacity tissue binding. The oral microdose of erythromycin failed to provide detectable plasma levels as a result of possible acid lability in the stomach. Absolute bioavailability for the 3 compounds examined yielded excellent concordance with data from the literature or data generated in house. CONCLUSION: Overall, when used appropriately, microdosing offers the potential to aid in early drug candidate selection.

Simultaneous determination of erythromycin propionate and base in human plasma by high-performance liquid chromatography-electrospray mass spectrometry.

An analytical method for simultaneous determination of erythromycin propionate and its active metabolite, erythromycin base, in human plasma by high-performance liquid chromatography-electrospray mass spectrometry (HPLC-ESI-MS) was developed and validated. Roxithromycin was selected as the internal standard. The samples were directly injected after simple deproteinized procedure only. The separation was achieved on a Johnson Spherigel analytical column packed with 5 microm C18 silica, employing acetonitrile -0.1% formic acid aqueous solution (50:50) as mobile phase. The quantification of target compounds was obtained by using a selected ion monitoring (SIM) at m/z 790.7 for erythromycin propionate, m/z 734.7 for erythromycin base and m/z 837.8 for roxithromycin. The correlation coefficients of the calibration curves were better than 0.997 (n=6), in the ranges from 2 ng/ml to 1 microg/ml, and from 1 to 10 microg/ml for erythromycin propionate and base. The method can provide the necessary sensitivity, precision and accuracy to allow the simultaneous determination of both compounds in a patient's plasma following a single administration of erythromycin stinoprate capsule (500 mg erythromycin base equivalent).

Hearing loss and erythromycin pharmacokinetics in a patient receiving hemodialysis.

A left upper lobe pneumonia developed in a patient who was receiving hemodialysis; he was treated intravenously with 1 g of erythromycin lactobionate every six hours. After five doses, hearing loss was noted; this was later documented by audiogram. Erythromycin serum concentrations as high as 100 mg/L and a half-life more than three times longer than normal were observed. To our knowledge, this represents the first report of reversible hearing loss associated with elevated serum erythromycin concentrations and prolonged serum half-life.

Erythromycin and clindamycin absorption and elimination in pregnant women.

Thirty-nine pregnant women admitted for therapeutic abortions during early or mid pregnancy were given erythromycin estolate, erythromycin base, or clindamycin hydrochloride orally in single or multiple doses. Peak serum levels of clindamycin were 3.4 to 9.0 mug/ml following a single dose of 450 mg, whereas peak serum levels of erythromycin were 0.29 to 7.2 mug/ml following 500 mg in a single dose. The individual variability of serum concentrations of erythromycin was greater than that reported in normal men and nonpregnant women, whereas the serum levels of clindamycin were rather uniform, and similar to what has been reported in nonpregnant individuals. Following multiple doses of each antibiotic, high serum levels were obtained in virtually all subjects, and urine levels were also higher. Following single doses the mean urinary recovery was 2% for erythromycin and 16.8% for clindamycin.