Probe Cocktail to Assess Transporter Function in Sandwich-Cultured Human Hepatocytes.

PURPOSE: Probe substrates are used routinely to assess transporter function in vitro. Administration of multiple probe substrates together as a "cocktail" in sandwich-cultured human hepatocytes (SCHH) could increase the throughput of transporter function assessment in a physiologically-relevant in vitro system. This study was designed to compare transporter function between cocktail and single agent administration in SCHH. METHODS: Rosuvastatin, digoxin, and metformin were selected as probe substrates of hepatic transporters OATP1B1, OATP1B3, BCRP, P-gp, and OCT1. Total accumulation (Cells+Bile) and biliary excretion index (BEI) values derived from administration of the cocktail were compared to values obtained after administration of single agents in the absence and presence of a model inhibitor, erythromycin estolate. RESULTS: For rosuvastatin and metformin accumulation, the ratio of means [90% confidence interval (CI)] for cocktail to single agent administration was 100% [94%, 106%] and 90% [82%, 99%], respectively. Therefore, the cocktail and single-agent mode of administration were deemed equivalent per standard equivalence criterion of 80-120% for rosuvastatin and metformin accumulation, but not for digoxin accumulation (77% [62%, 92%]). The ratio of means [90% CI] for rosuvastatin BEI values between the two administration modes (105% [97%, 114%]) also was deemed equivalent. The ratio for digoxin BEI values between the two administration modes was 99% [78%, 120%]. In the presence of erythromycin estolate, the two administration modes were deemed equivalent for evaluation of rosuvastatin, digoxin, and metformin accumulation; the ratio of means [90% CI] was 104% [94%, 115%], 94% [82%, 105%], and 100% [88%, 111%], respectively. However, rosuvastatin and digoxin BEI values were low and quite variable in the presence of the inhibitor, so the BEI results were inconclusive. CONCLUSIONS: These data suggest that rosuvastatin and metformin can be administered as a cocktail to evaluate the function of OATP1B1, OATP1B3, BCRP, and OCT1 in SCHH, and that digoxin may not be an ideal component of such a cocktail.

Pharmacokinetics of erythromycin after the administration of intravenous and various oral dosage forms to dogs.

The purpose of this study was to describe and compare the pharmacokinetic properties of different formulations of erythromycin in dogs. Erythromycin was administered as lactobionate (10 mg/kg, IV), estolate tablets (25 mg/kg p.o.) and ethylsuccinate tablets or suspension (20 mg/kg p.o.). After intravenous (i.v.) administration, the principal pharmacokinetic parameters were (mean +/- SD): AUC((0-infinity)) 4.20 +/- 1.66 microg x h/mL; C(max) 6.64 +/- 1.38 microg/mL; V(z) 4.80 +/- 0.91 L/kg; Cl(t) 2.64 +/- 0.84 L/h.kg; t((1/2)lambda) 1.35 +/- 0.40 h and MRT 1.50 +/- 0.47 h. After the administration of estolate tablets and ethylsuccinate suspension, the principal pharmacokinetic parameters were (mean +/- SD): C(max), 0.30 +/- 0.17 and 0.17 +/- 0.09 microg/mL; t(max), 1.75 +/- 0.76 and 0.69 +/- 0.30 h; t((1/2)lambda), 2.92 +/- 0.79 and 1.53 +/- 1.28 h and MRT, 5.10 +/- 1.12 and 2.56 +/- 1.77 h, respectively. The administration of erythromycin ethylsuccinate tablets did not produce measurable serum concentrations. Only the i.v. administration rendered serum concentrations above MIC(90) = 0.5 microg/mL for 2 h. However, these results should be cautiously interpreted as tissue erythromycin concentrations have not been measured in this study and, it is recognized that they can reach much higher concentrations than in blood, correlating better with clinical efficacy.

Ocular inserts for controlled release of antibiotics.

Ocular inserts impregnated with antibiotics (erythromycin and erythromycin estolate) which have sustained release characteristics were prepared, mainly for the purpose of trachoma therapy. In vitro experiments showed that the elution rate of a drug with low solubility in water (erythromycin estolate) is constant when the water content of the hydrogel insert is more than 30%. In the case of a drug with higher solubility (erythromycin), the elution rate depends on the water content. Some in vivo experiments using rabbit eyes were also reported.

In vivo evaluation of ocular inserts of hydrogel impregnated with antibiotics for trachoma therapy.

Sustained release of antibiotics from hydrogel matrices in the eye was studied for the purpose of developing a new method for trachoma therapy. Copolymers of N-vinylpyrrolidone were moulded into an ocular insert and impregnated with erythromycin or erythromycin estolate. The antibiotic-hydrogel inserts completely suppressed the chlamydia trachomatis infection in the owl monkey eyes. The drug elution rates were a little lower in vivo than in vitro. By comparison of the drug elution rate in the human eye with that in the owl monkey eye, similar therapeutic effect is expected in the treatment of human trachoma.

Comparative bioavailability evaluation of erythromycin base and its salts and esters. I. Erythromycin estolate capsules versus enteric-coated erythromycin base tablets.

A randomized crossover study in 16 healthy volunteers given multiple doses of erythromycin base enteric-coated tablets or erythromycin estolate capsules revealed essentially no difference in the resultant plasma concentration of bioactive erythromycin. This similarity in bioactivity persisted despite the fact that total eryghromycin levels (bioactive erythromycin base plus bioinactive erythromycin propionate) were at least three times higher after administration of the estolate than after administration of the base.

Topically applied antibiotics in acne vulgaris: clinical response and suppression of Corynebacterium acnes in open comedones.

Topical antibiotics were used on patients with acne vulgaris. Corynebacterium acnes organisms from open comedones were quantitated during treatment, and the progress of the disease was evaluated. Clindamycin lotion completely suppressed the growth of C acnes organisms, whereas erythromycin and tetracycline did not depress the C acnes counts. Taken as a group, these antibiotics gave a substantial improvement of the disease on the treated side as compared with paired untreated sides of the face and back.

Plasma levels following single and repeated doses of erythromycin estolate and erythromycin stearate.

The pharmacokinetics of erythromycin and erythromycin 2'-propanoate were studied in healthy male volunteers following single and repeated doses of erythromycin stearate tablets, erythromycin estolate capsules, and a suspension. Estolate dosages gave rise to higher plasma levels of total drug than the stearate. However, the stearate yielded higher plasma levels of erythromycin base. Absorption of all dosage forms, except the suspension, was delayed, and pharmacokinetic interpretation of both single- and multiple-dose data required incorporation of an absorption lag time. The absorption of erythromycin stearate was inhibited by food and also by low fluid volumes in fasted subjects. Absorption of erythromycin estolate was increased in the presence of food and was not greatly affected by fluid volume. Although single-dose data poorly predicted circulating levels of erythromycin following repeated doses, trends observed after single doses were maintained during chronic treatment.

Protective effect of Livex, a herbal formulation against erythromycin estolate induced hepatotoxicity in rats.

Livex, a compound herbal formulation, was investigated for its possible hepatoprotective effect in Wistar rats against erythromycin estolate induced toxicity. Oral administration of Livex significantly prevented the occurrence of erythromycin estolate induced hepatic damage. The increased level of serum enzymes (aspartate transaminase, alanine transaminase, alkaline phosphatase), bilirubin, serum and tissue cholesterol, triglycerides, phospholipids and free fatty acids observed in rats treated with erythromycin estolate were very much reduced in rats treated with Livex and erythromycin estolate. These biochemical observations were supplemented by histopathological examination of liver sections. Results of this study revealed that Livex could afford a significant protection against erythromycin estolate induced hepatocellular damage.

Equine proliferative enteropathy: a cause of weight loss, colic, diarrhoea and hypoproteinaemia in foals on three breeding farms in Canada.

Proliferative enteropathy (PE) is a transmissible enteric disease caused by Lawsonia intracellularis. An outbreak of equine PE was diagnosed in foals from 3 breeding farms. Most foals had been weaned prior to the appearance of clinical signs, which included depression, rapid and marked weight loss, subcutaneous oedema, diarrhoea and colic. Poor body condition with a rough haircoat and a potbellied appearance were common findings in affected foals. Respiratory tract infection, dermatitis and intestinal parasitism were also found in some foals. Haematological and plasma biochemical abnormalities included hypoproteinaemia, transient leucocytosis, anaemia and increased serum creatinine kinase concentration. Postmortem diagnosis of PE was confirmed on 4 foals based on the presence of characteristic intracellular bacteria within the apical cytoplasm of proliferating crypt epithelial cells of the intestinal mucosa, using silver stains, and by results of PCR analysis and immunohistochemistry. Antemortem diagnosis of equine PE was based on the clinical signs, hypoproteinaemia and the exclusion of common enteric infections. Faecal PCR analysis was positive for the presence of L. intracellularis in 6 of 18 foals tested while the serum of all 7 foals with PE serologically evaluated had antibodies against L. intracellularis. Most foals were treated with erythromycin estolate alone or combined with rifampin for a minimum of 21 days. Additional symptomatic treatments were administered when indicated. All but one foal treated with erythromycin survived the infection. This study indicates that equine PE should be included in the differential diagnosis of outbreaks of rapid weight loss, diarrhoea, colic and hypoproteinaemia in weanling foals.

Comparison of erythromycin ethyl succinate, stearate and estolate treatments of group A streptococcal infections of the upper respiratory tract.

The microbiologic and clinical responses of acute Group A beta-hemolytic streptococcal infections of the upper respiratory tract to oral treatment with erythromycin ethyl succinate, stearate, and estolate were studied in 303 patients. Streptococcal M and T typing was done on all positive cultures. The overall cure rate was 95.4 per cent, with no statistically significant differences in clearing organisms from the pharynx. Of the 285 cured patients who completed the prescribed follow-up period, 11 had recurrences between the 12th and 31st day after initiation of therapy, and five developed new infections. No cases of rheumatic fever or glomerulonephritis were encountered during a follow-up study. Eight gastrointestinal reactions and one transient rash occurred. Results with these forms of erythromycin compare favorably with published results for similar infections treated with oral penicillins.

[Comparison of the bioavailabilities of erythromycin estolate and erythromycin ethylsuccinate dry suspension preparations in steady state]. / Vergleich der Bioverfügbarkeiten von Erythromycinestolat bzw. Erythromycinethylsuccinat enthaltenden Trockensaft-Zubereitungen im steady state.

Relative bioavailability of erythromycin was determined after multiple-dose administration of erythromycin estolate in comparison to erythromycin ethylsuccinate both given as oral suspensions to twelve healthy volunteers. The daily erythromycin dose of erythromycin ethylsuccinate was 50% higher than the respective dose of erythromycin estolate; the dosage interval tau was 12 h for erythromycin estolate and 8 h for erythromycin ethylsuccinate. This scheme was planned in accordance to advices of the respective manufactures. Results of the study confirm the differences in extent of bioavailability of both erythromycin derivatives known from single-dose investigations. Furthermore, the experimental data show that a twice daily administration of 1000 mg erythromycin as erythromycin estolat resulted in sufficiently high plasma concentration of the active compound.

Absorption of erythromycin. A cross-over study in healthy volunteers.

The absorptions of 6 erythromycin preparations were compared in a cross-over study in healthy humans. In a single-dose study, 500 mg of each preparation was, after an overnight fast, given to 10 volunteers. The two enterosoluble preparations of erythromycin base studied were absorbed slowly, and the peak serum concentration (1.5-2 mg/l) was achieved only at 4 h. The absorption of the stearates was quick, but especially one of them was poorly absorbed, the serum concentration being always below 1 mg/l. Both of the two estolates gave highest apparent concentrations, and the maximum serum level (2-2.5 mg/l) was achieved at 2 h, but the concentration of active erythromycin remains unknown. In the second part of the study, two erythromycin stearates and one base preparation were given at 6-h interval in a cross-over fashion, each for 4 days. On the 4th day, blood samples were analyzed. The erythromycin base gave higher serum concentrations than did the two stearates, which were equivalent. It seems doubtful that the erythromycin stearate at the dose of 250 mg every 6th hour would give satisfactory serum levels of erythromycin which would be effective against most bacteria during the whole treatment.

Selection of an oral erythromycin product.

The chemistry, bioavailability, and adverse effects of erythromycin base, stearate, estolate, and ethylsuccinate are reviewed. Criteria for the evaluation of erythromycin bioavailability studies include study design, patient population, meal composition and timing, and assay methodology. Based on these criteria, the bioavailability of individual erythromycin products are evaluated in this paper. Compared with other antibiotics, the erythromycins have a good safety record. However, both the estolate and ethylsuccinate forms of erythromycin may cause hepatotoxity. Considering bioavailability and adverse effect data, a specific brand of enteric-coated erythromycin base tablets is recommended for erythromycin-sensitive infections in adults. For pediatric patients, a liquid formulation of erythromycin estolate or erythromycin ethylsuccinate is recommended.

Streptococcal pharyngitis therapy. A comparison of two erythromycin formulations.

The recommended dosage of erythromycin, without regard to the formulation prescribed, for children with streptococcal pharyngitis is 30 to 40 mg/kg/day. We previously reported an acceptable streptococcal eradication rate among patients with pharyngitis treated with erythromycin estolate, 20 mg/kg/day. In this study, an extension of the earlier one, the efficacy of this same dosage of erythromycin estolate was compared with a 40 mg/kg/day dosage of erythromycin ethylsuccinate. Streptococcal eradication rates were nearly identical in the two groups of patients. The efficacy of erythromycin estolate at a dosage lower than that recommended for children is most likely explained on pharmacologic grounds: better absorption and higher levels in serum and tissue than those achieved with other erythromycin formulations. It seems rational to calculate required dosages of erythromycin on the basis of the formulation being administered.

Topical sulfacetamide vs oral erythromycin for neonatal chlamydial conjunctivitis.

Conjunctival and nasopharyngeal cultures for Chlamydia trachomatis were obtained from infants 30 days of age or younger with purulent conjunctivitis. Conjunctival specimens were also tested for other bacterial pathogens and for viruses. Most of the infants studied were black and came from a low-income, urban population. By random assignment infants received either topical treatment with 10% sulfacetamide sodium ophthalmic solution or systemic treatment with oral erythromycin estolate (50 mg/kg/day). Treatment was continued for 14 days if C trachomatis was isolated from the conjunctivae. Treatment was considered to be effective if conjunctivitis resolved and if follow-up chlamydial cultures of the conjunctivae and nasopharynx were negative at completion of therapy and two to four weeks later. Chlamydia trachomatis was isolated in the absence of other pathogens from the eyes of 37 (73%) of 51 infants with conjunctivitis. Other bacterial pathogens were isolated from four infants (8%) and viruses from none. Chlamydial infection was eradicated from 14 (93%) of 15 infants treated orally. In contrast, persistent conjunctival infection was detected in eight infants (57%) and nasopharyngeal colonization in three (21%) of 14 infants after topical treatment. It was concluded that C trachomatis is the most frequent cause of neonatal conjunctivitis in the low-income, urban population studied; that erythromycin estolate administered orally for 14 days eradicates chlamydial conjunctival and nasopharyngeal infection; and that topical sulfacetamide therapy may result in persistent conjunctival infection and nasopharyngeal colonization.

The release of insoluble antibiotics from collagen ocular inserts in vitro and their insertion into the conjunctival sac of cattle.

The release rate of procaine penicillin, erythromycin and erythromycin estolate from soluble and insoluble collagen films was investigated in vitro to develop an ocular insert for the treatment of infectious bovine keratoconjunctivitis. The release rate and duration of release varied according to the selection of antibiotic and vehicle. The combination of erythromycin estolate and soluble collagen produced the most sustained drug-delivery system. However, due to the inappropriate physical properties of collagen and poor retention of ocular inserts, it was considered that the development of an antibiotic-impregnated collagen ocular insert requires further investigation.

Concentrations of erythromycin in serum and tonsil: comparison of the estolate and ethyl succinate suspensions.

Concentrations of erythromycin were measured in serum and tonsil from children who had received either the estolate or ethyl succinate suspension before surgery. The in vitro assay measured total erythromycin activity against a group A beta hemolytic streptococcus. Levels of erythromycin in serum and tonsil after single and multiple doses of the estolate were significantly higher than those after administration of the ethyl succinate. The therapeutic implications of these findings are unknown.

Seven days of erythromycin estolate is as effective as fourteen days for the treatment of Bordetella pertussis infections.

OBJECTIVE AND METHODS: Although 14 days of erythromycin is recommended for the treatment of Bordetella pertussis infection, there have been no prospective controlled studies to support the contention that this long course of therapy is required to eradicate the microorganism from the nasopharynx or to prevent bacteriological relapse. We randomly allocated children and adults with culture-positive community-acquired pertussis to either 7 or 14 days of erythromycin estolate treatment (40 mg/kg/d; maximum dose 1 g/d). Nasopharyngeal aspirate cultures were obtained by study nurses during home visits before and at the end of treatment, and 1 week after the completion of treatment. B pertussis-specific antibodies were measured before treatment and 1 month later. Information about clinical symptoms, adverse reactions, and compliance were collected at each scheduled contact. RESULTS AND CONCLUSIONS: A total of 168 participants were eligible for analysis (74 treated for 7 days and 94 treated for 14 days). Bacteriological persistence (positive end of therapy culture) occurred once in each group, and bacteriological relapse (positive culture 1 week after completion of treatment) occurred in one participant treated for 7 days. The overall failure rate (persistence plus relapse) of 2.70% in the 7-day group was not different than the rate of 1.06% in the 14-day group. The study had a power of 99.99% at the 5% level to detect a difference in failure rates of 10% and a power of 80% to detect a difference of 5%. We conclude that 7 days of erythromycin estolate is as effective as 14 days for the eradication of B pertussis.