Pharmacokinetics of pivmecillinam.

Parsons, R. L.; Hossack, GA; Paddock, GM

doi:10.1111/j.1365-2125.1977.tb00711.x

Cited by 11 publications

(6 citation statements)

References 11 publications

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“…(1) recovered only 15% of an intramuscular dose in the urine over 6 h. A partial explanation for the lower urinary recoveries found by others is most likely due to the instability of mecillinam in urine (1,6,9). Furthermore, our percentage of the dose recovered in the urine was calculated after correcting for the administered dose.…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetics of mecillinam in health subjects

Gambertoglio¹,

Barriere²,

Lin³

et al. 1980

Antimicrob Agents Chemother

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Mecillinam is an amidino penicillinate derivative with a broad spectrum of activity against many gram-negative bacilli. Moreover, marked in vitro synergy against these organisms occurs when mecillinam is combined with other ,B-lactam antibiotics. The purpose of this study was to determine the pharmacokinetic disposition of this antibiotic. A single dose of 10 mg/kg was administered to 12 healthy volunteers as a 15-min intravenous infusion. Multiple plasma and urine samples were collected at frequent intervals for 8 and 24 h, respectively. Plasma samples were assayed for mecillinam by using a specific high-pressure liquid chromatographic assay developed in our laboratory. Peak plasma levels ranged from 34 to 80 Ag/ml, and after 4 h, plasma levels were 0.7 to 1.9 ,g/ml. The mean terminal plasma half-life was 51.1 ± 8.6 min. The mean steady-state volume of distribution was calculated to be 0.23 ± 0.04 liter/kg. The mean plasma and renal clearances were 3.5 ± 0.4 and 2.5 ± 0.4 ml/min per kg, respectively. The mean percentage of the dose excreted unchanged in the urine at 4 h was 67 ± 5%; 71 ± 6% was recovered in 24 h. Urine concentrations at 4 h were far above the minimum inhibitory concentration for susceptible gram-negative organisms.Mecillinam is a new semisynthetic /8-lactam antibiotic. It is a 6-amidinopenicillanic acid, whereas other 8l-lactam antibiotics are 6-acylaminopenicillanic acids. This altered structure has resulted in differences in microbiological activity. Mecillinam is generally more active against gram-negative than gram-positive organisms. The minimum inhibitory concentration of mecillinam for most susceptible strains of gram-negative bacteria is c1 to 2 pg/ml (9). Additionally, this antibiotic exhibits synergistic effects in vitro when combined with other 8-lactam antibiotics such as ampicillin, carbenicillin, or cephalothin (2).The objectives of this study were to determine the pharmacokinetic parameters and excretion characteristics of mecillinam after intravenous administration in healthy subjects. This was accomplished by using a newly developed highpressure liquid chromatographic assay developed by our group for determination of mecillinam in plasma and urine.(This paper was presented in part at the 81st Annual Meeting of the American Society for Clinical Pharnacology and Therapeutics, San Francisco, Calif., March 19, 1980.) MATERIALS AND METHODS Experimental procedure. Twelve healthy adult volunteers participated in this study. Informed consent was obtained from each subject, and guidelines for human experimentation of the U.S. Department of Health, Education, and Welfare and those of our institution were followed in the conduct of this clinical research. A panel of laboratory tests, consisting of an SMA 12, complete blood cell count, differential blood cell count, urinalysis, and creatinine clearance, as well as a complete medical history and physical examination were performed before and after drug administration. Table 1 shows individual subject characteristics. Mecillinam (1-g vial...

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Section: Resultsmentioning

confidence: 99%

Pharmacokinetics of mecillinam in health subjects

Gambertoglio¹,

Barriere²,

Lin³

et al. 1980

Antimicrob Agents Chemother

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“…Ampicillin suspension , aspirin enteric-coated granules, and digoxin elixir are included in this category, while encapsulated, enteric-coated tablets, or tablet dosage forms of Greenblatt et al (1974) Ethambutol Tablets Ameer et al (1982) Hydralazine Tablets Walden et al (1981) Indoprofen Tablets Johnson et al (1978) Oxazepam Tablets Melander et al (1977e) Oxpi'enolol Conventional and sustained Dawes et al (1979) release tablets Penicillin V (acid) Tablets Peck et al (1958) Phenazone (antipyrine) Combination tablets Melander et al (1977a) Pivampicillin Capsules Roholt et al (1974) Pivmecillinam Parsons et a!. (1977) Prednisone Tablets Tembo et al (1976) Propylthiouracil Tablets Melander et al (1977g) Spiramycin Tablets Kamme et al (1978) Sulphasomidine Tablets Melander et al (1976b) Theophylline Tablets Welling et al (1975a) Tolbutamide Tablets Sartor et al (1980) Tranexamic acid Tablets Pilbrant et al (1981) a Studied in children.…”

Section: Interactions Having No Effect On Drug Absorptionmentioning

confidence: 98%

Interactions Affecting Drug Absorption

Welling¹

1984

Clinical Pharmacokinetics

157

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The influence of drug-drug and drug-food interactions affecting the absorption of orally administered medication is reviewed. Drug-drug interactions can be classified in terms of indirect effects by one drug on gastrointestinal tract physiology influencing the absorption of other drugs, or direct interactions involving altered pH, adsorption, absorption, or chelation. Most, but not all, drug-drug interactions result in reduced or delayed systemic drug availability. Drug-food interactions may result in reduced, delayed, or increased systemic drug availability. The absorption of only a small number of drugs is unaffected by concomitant food intake. The degree of interaction and whether it positively or negatively affects drug absorption depends on a number of factors including the physical and chemical nature of the drug, the formulation, the type of meal, and the time interval between eating and dosing. Mechanisms of drug-food interactions are not well characterised. They clearly involve both direct and indirect factors in a similar fashion to drug-drug interactions, but indirect factors probably predominate. Reduced or delayed drug absorption is generally attributed, at least in part, to delayed stomach-emptying due to food. Increased absorption may also result from delayed stomach-emptying facilitating greater drug dissolution before it passes from the stomach into the small intestine. Increased bioavailability of some drugs, e.g. propranolol, metoprolol and labetalol, may be related to reduced presystemic clearance. The potential clinical implications of drug-drug and drug-food interactions must be taken into account with oral medications in order to minimise variations in systemic drug availability and hence in clinical efficacy.

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“…For the quantification of mecillinam, several methods have been reported [6–9, 14–17]. Most of them was performed using agar diffusion method [6–9, 14, 15], which was nonspecific and required special laboratory conditions for their routine use. Two papers [16, 17] reported methods to determine mecillinam in human plasma by HPLC‐UV, which were not sensitive enough for the human pharmacokinetic studies (the concentration of mecillinam in plasma could decreased to 144 ng/ml after four half‐lives).…”

Section: Introductionmentioning

confidence: 99%

“…Pivmecillinam, a 6-acylamidinopenicillanic acid ester belonging to β-lactam antibiotics, is well absorbed after oral administration [5]. In vivo, this biologically inactive compound is hydrolyzed by nonspecific intestinal esterase to the biologically active mecillinam [6][7][8]. Contrary to most penicillin, mecillinam exerts a significant activity against Gram-negative organisms but low activity against Gram-positive bacteria [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

LC‐MS/MS methods for determination of unstable pivmecillinam and mecillinam in acidified human plasma: Application to a pharmacokinetic study

Sun

Zhao

Gao

et al. 2022

J of Separation Science

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Pivmecillinam, the ester of biologically active antibiotic mecillinam, is an effective oral preparation to treat urinary tract infections. To study pharmacokinetics in humans, LC‐MS/MS methods were developed to quantify pivmecillinam and mecillinam in human plasma, respectively. Considering cephalexin as internal standard, analytes were separated on UltimateXB‐C18 columns after protein precipitation by acetonitrile. The mobile phase was composed of water containing 0.1% formic acid and methanol. The multiple reactions monitoring transitions of m/z 440.2→167.1, 326.1→167.1, and 348.1→158.1 were selected to inspect pivmecillinam, mecillinam, and the internal standard in positive ion mode. No apparent matrix effect was perceived. Linearities were obtained over calibration ranges of 0.0500–12.0 and 10.0–15,000 ng/mL, respectively. The intraday precisions were below 5.5%, the interday precisions were below 6.1%, and accuracies were within –8.1 to 13.0%. Stability tests were conducted and an acidification step was explored to enhance the stability of pivmecillinam and mecillinam. Further stability was validated under various storage and processing conditions. Both methods were applied to a pharmacokinetic study of pivmecillinam and mecillinam after oral administration of 400 mg pivmecillinam hydrochloride tablets in healthy Chinese subjects.

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Pharmacokinetics of pivmecillinam.

Cited by 11 publications

References 11 publications

Pharmacokinetics of mecillinam in health subjects

Pharmacokinetics of mecillinam in health subjects

Interactions Affecting Drug Absorption

LC‐MS/MS methods for determination of unstable pivmecillinam and mecillinam in acidified human plasma: Application to a pharmacokinetic study

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