Intersubject and dose‐related variability after intravenous administration of erythromycin.

Austin, K. L.; Mather, Laurence E.; Philpot, C. R.; McDonald, PJ

doi:10.1111/j.1365-2125.1980.tb01755.x

Cited by 109 publications

(47 citation statements)

References 14 publications

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“…This may account, at least in part, for the nonlinearity of clarithromycin pharmacokinetics. Similar nonlinear pharmacokinetics have been noted for the macrolide erythromycin (3,10). CLRs of both the parent drug and the metabolite showed statistically significant differences between some dose groups, very possibly due to the different subjects used in each group, because further correlation st-order renal elimina-…”

Section: Discussionmentioning

confidence: 51%

Pharmacokinetics of clarithromycin, a new macrolide, after single ascending oral doses

Chu

Sennello

Bunnell

et al. 1992

Antimicrob Agents Chemother

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The pharmacokinetics and safety of single ascending doses of clarithromycin (6-0-methylerythromycin A) were assessed in a placebo-controlled, double-blind, randomized trial with 39 healthy male volunteers. Subjects were randomized to receive single doses of either placebo or 100, 200, 400, 600, 800, or 1,200 mg of clarithromycin. Blood and urine collections were performed over the 24 h following administration of the test preparation. Biological specimens were analyzed for clarithromycin and 14(R)-hydroxyclarithromycin content by a high-performance liquid chromatographic technique. The pharmacokinetics of clarithromycin appeared to be dose dependent, with terminal disposition half-life ranging from 2.3 to 6.0 h and mean ± standard deviation area under the concentration-versus-time curve from time 0 to infinity for plasma ranging from 1.67: 0.48 to 3.72 t 1.26 mgtliter. h per 100-mg dose over the 100-to 1,200-mg dose range. Similar dose dependency was noted in the pharmacokinetics of the 14(R)-hydroxy metabolite. Mean urinary excretion of clarithromycin and its 14(R)-hydroxy metabolite ranged from 11.5 to 17.5% and 5.3 to 8.81% of the administered dose, respectivety. Urinary excretion data and plasma metabolite/parent compound concentration ratio data suggested that capacity-limited formation of the active metabolite may account, at least in part, for the nonlinear pharmacokinetics of darithromycin. No substantive dose-related trend was observed for the renal clearance of either compound. There were no clinically significant drug-related alterations in laboratory and nonlaboratory safety parameters. In addition, there was no significant difference between placebo and clarithromycin recipients in the incidence or severity of adverse events. Clarithromycin appears to be safe and well tolerated.The new 14-membered macrolide antimicrobial agent clarithromycin (A-56268, TE-031) is active in vitro against several important gram-positive and gram-negative pathogens, such as Streptococcus pyogenes, Staphylococcus aureus, Haemophilus species, Legionella species, Mycobacterium avium complex, and Chlamydia species (2, 4, 6, 8-10, 16, 19). Clarithromycin is active intracellularly, and its action is static or bactericidal, depending on the organism and antimicrobial agent concentration (2). Clarithromycin is more acid stable than erythromycin and in animal models achieves higher concentrations in plasma and tissue than erythromycin, especially in the lung (12, 13,15). The Food and Drug Administration-approved dosage regimen for clarithromycin ranges from 250 to 500 mg twice daily (respiratory tract and skin or skin structure infections).The present study was designed to assess the pharmacokinetics and safety of oral clarithromycin in a single-ascending-dose study in healthy young adult male volunteers.( graphy, and audiometry criteria. No subjects were receiving chronic medication.The study was approved by the Institutional Review Board of Quincy Research Center, Kansas City, Mo., and all subjects provided written, informed...

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Section: Discussionmentioning

confidence: 51%

Pharmacokinetics of clarithromycin, a new macrolide, after single ascending oral doses

Chu

Sennello

Bunnell

et al. 1992

Antimicrob Agents Chemother

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“…Biliary recycling of erythromycin base has been demonstrated (19) or suggested by different authors (2,21,23). This phenomenon was seen but not commented on in other papers (8,18).…”

Section: Methodsmentioning

confidence: 77%

Pharmacokinetic advantages of erythromycin estolate over ethylsuccinate as determined by high-pressure liquid chromatography

Croteau

Bergeron

LeBel

1988

Antimicrob Agents Chemother

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The pharmacokinetics of erythromycin estolate (500 mg) and erythromycin ethylsuccinate (600 mg) were compared in 12 healthy volunteers after single doses and after repeated oral doses (every 8 h). High-pressure liquid chromatography with electrochemical detection was used to determine concentrations in plasma and urine of estolate, ethylsuccinate, and erythromycin base. The maximum concentration of drug in the serum, the half-life, and the area under the curve for erythromycin estolate were significantly greater than those of erythromycin ethylsuccinate after both regimens. After single and multiple doses, the respective areas under the curve of erythromycin base generated by estolate formulation were 3 and 1.6 times greater (P < 0.05) than those of ethylsuccinate. The lower percentage of hydrolysis of erythromycin estolate (41 versus 69%) combined with its longer half-life (5.47 versus 2.72 h) and its larger area under the curve (30.61 versus 4.68 ,ig * h/ml, after multiple doses) could explain these differences. This study underscores the need for a specific high-pressure liquid chromatography assay and the importance of wide variability, rate-limited processes, changes with multiple doses, and the appearance of a second peak when one studies the pharmacokinetics of erythromycin esters. The pharmacokinetic data presented in this study reinforce the clinical advantages of erythromycin estolate over erythromycin ethylsuccinate.Recent clinical trials suggest that erythromycin estolate is more effective than erythromycin ethylsuccinate in the treatment of streptococcal pharyngitis (13,15

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“…CYP3A4, the predominant cytochrome P450 catalyst of oxidative metabolism in human liver, is expressed at a higher protein and mRNA level in women than in men (Hunt et al, 1992;Wolbold et al, 2003;Diczfalusy et al, 2008). Accordingly, certain CYP3A4 drug substrates, including cyclosporine (Kahan et al, 1986), erythromycin (Austin et al, 1980), and nifedipine (Krecic-Shepard et al, 2000), show higher clearance rates in women. CYP3A4-catalyzed hepatic microsomal N-dechloroethylation of the anticancer drug ifosfamide is also more rapid in women, suggesting that women could be more susceptible to the neurotoxic side affects associated with this metabolic pathway (Schmidt et al, 2001).…”

Section: Sex Differences In Hepatic Drug Metabolismmentioning

confidence: 99%

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Waxman

Holloway²

2009

Mol Pharmacol

618

584

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Sex differences in pharmacokinetics and pharmacodynamics characterize many drugs and contribute to individual differences in drug efficacy and toxicity. Sex-based differences in drug metabolism are the primary cause of sex-dependent pharmacokinetics and reflect underlying sex differences in the expression of hepatic enzymes active in the metabolism of drugs, steroids, fatty acids and environmental chemicals, including cytochromes P450 (P450s), sulfotransferases, glutathione transferases, and UDP-glucuronosyltransferases. Studies in the rat and mouse liver models have identified more than 1000 genes whose expression is sex-dependent; together, these genes impart substantial sexual dimorphism to liver metabolic function and pathophysiology. Sex differences in drug metabolism and pharmacokinetics also occur in humans and are due in part to the female-predominant expression of CYP3A4, the most important P450 catalyst of drug metabolism in human liver. The sexually dimorphic expression of P450s and other liver-expressed genes is regulated by the temporal pattern of plasma growth hormone (GH) release by the pituitary gland, which shows significant sex differences. These differences are most pronounced in rats and mice, where plasma GH profiles are highly pulsatile (intermittent) in male animals versus more frequent (nearly continuous) in female animals. This review discusses key features of the cell signaling and molecular regulatory mechanisms by which these sex-dependent plasma GH patterns impart sex specificity to the liver. Moreover, the essential role proposed for the GH-activated transcription factor signal transducer and activator of transcription (STAT) 5b, and for hepatic nuclear factor (HNF) 4␣, as mediators of the sexdependent effects of GH on the liver, is evaluated. Together, these studies of the cellular, molecular, and gene regulatory mechanisms that underlie sex-based differences in liver gene expression have provided novel insights into the physiological regulation of both xenobiotic and endobiotic metabolism.

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Intersubject and dose‐related variability after intravenous administration of erythromycin.

Cited by 109 publications

References 14 publications

Pharmacokinetics of clarithromycin, a new macrolide, after single ascending oral doses

Pharmacokinetics of clarithromycin, a new macrolide, after single ascending oral doses

Pharmacokinetic advantages of erythromycin estolate over ethylsuccinate as determined by high-pressure liquid chromatography

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

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