Journal of Chemotherapy
ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20
Pharmacokinetics and Tissue Distribution of Amoxicillin plus Clavulanic Acid after Oral Administration in Man F. Fraschini, F. Scaglione, M. Falchi, S. Dugnani, M. Mezzetti, F. Cicchetti, G. Alfano & G.P. Pintucci To cite this article: F. Fraschini, F. Scaglione, M. Falchi, S. Dugnani, M. Mezzetti, F. Cicchetti, G. Alfano & G.P. Pintucci (1990) Pharmacokinetics and Tissue Distribution of Amoxicillin plus Clavulanic Acid after Oral Administration in Man, Journal of Chemotherapy, 2:3, 171-177, DOI: 10.1080/1120009X.1990.11739013 To link to this article: http://dx.doi.org/10.1080/1120009X.1990.11739013
Published online: 17 Jan 2017.
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Date: 18 April 2017, At: 00:01
Journal of Chemotherapy
Pharmacokinetics and Tissue Distribution of Amoxicillin plus Clavulanic Acid after Oral Administration in Man F. FRASCHINI * - F. SCAGLIONE * M. FALCHI * - S. DUGNANI * M. MEZZETTI ** - F. CICCHETTI *** G. ALFANO *** - G.P. PINTUCCI **** Summary ---------------------------------Augmentin (875 amoxicillin and 125 mg potassium clavulanate) was administered orally to patients with chronic bronchitis. Concentrations of amoxicillin and clavulanic acid were measured in serum, sputum and urine . P eak serum levels for amoxicillin of 11.23 ± 2.61 f!g/ml were observed at 2 hours and for clavulanic acid of 2.55 ± 0.54 Jlg/ml at 1 hour. After 9 hours, 50% of the amoxicillin and 39% of the clavulanic acid had been renally excreted. The peak sputum concentration of amoxicillin was 1.31 ± 0.42 Jlg/ml at 4 hours and of clavulanate was 0. 79 ± 0.23 Jlg/ml at 2 hours. Patients awaiting surgery received an oral dose of augmentin as above. Samples of lung, tonsil, middle ear mucosa and prostate were obtained and tissue concentrations of both compounds measured. Peak levels of amoxicillin ranged from 0. 87 Jlg/g (tonsil) to 2.56 Jlg/g (lung) and of clavulanic acid from 0.20 Jlg/g (prostate) to 0.56 Jlg/g (lung) between 3 and 4 hours aft er dosing. Key words: Amoxicillin, clavulanate, augmentin, pharmacokinetics.
* D epartment of Pharmacology, Chemotherapy and Toxicology, University of Milan, Italy. ** Di vision of Chest Surgery, Policlinico Hospital, Mi lan, Italy. *** Division of Urology, Bassini Hospital, Milan, Italy. **** E .N.T. Division, Hospital of Vimercate, Vimercate (Milan), Italy. Correspondence: Prof. Franco Fraschini, Chair of Chemotherapy, Department of Pharmacology, Via Vanvitetli 32, 20129 Milano, Italy. © Edizioni Ri viste Scientifiche · Firenze
Vol. 2 · n. 3 (171 -177) · 1990
INTRODUCTION
The availability of preparations characterized by low toxicity coupled with high intrinsic ac tivity and high resistance to inactivation by bacterial enzymes has enhanced current antibacterial therapy. Clavulanic acid 1 • 2 , itself structurally related to the penicillins, h as little intrinsic antibacterial activity. However, it behaves as a high affinity substrate for bacterial ~ -lactamases 3 • 4 and h as the ability to protect ~ -l actam antibiotics from enzymic destruction. Thus the use of clavulanic acid in combination preparations has increased the potential therapeutic value of penicillins against ~ -lactamase producing organisms. Penicillins co-administered with a ~ - lacta mase inhibitor have been widely used to treat infections due to various pathogens. The most extensively investigated among these preparations is the combination of amoxicillin and clavulanic acid (augmentin) '· 6 , which may be administered either orally or intravenously . The serum pharmacokinetics of this combination have already been extensively investigated and the substantial kinetic compatibility of the two components has been confirmed 7 • 8 • In contrast, however, there are fewer studies on the distribution of amoxicillin and clavulanic acid in tissue compartments or in fluids other than blood 9 • 10 , particularly when given by the oral route. Therefore a multicenter study was set up to investigate distribution in tissues after oral administration of augmentin . Levels of both amoxicillin and clavulanic acid were determined in sputum and in lung, tonsil, prostate and middle ear mucosa . In addition, serum pharmaJSSN I t20-009X
172
F . FRASCHINI - F . SCAGLIO NE,
cokinetics and urinary excretion were determined to confirm existing work. We now present a full report of our earlier preliminary studies 11 • MATERIALS AND METHODS
The study was carried out in accordance with the Helsinki Declaration.
et aJii
centrations of amoxicillin and clavulanic acid in serum, sputum and urine were determined using the microbiological assay method described by Jackson et al. 12 • An image analysis system (BLC) was used to read inhibition zone areas and all assays were performed in triplicate. The pharmacokinetics of amoxicillin and clavulanic acid in serum and sputum were determined with a first-order, one-compartment open model, using a curve-fitting computer program.
Body fluid distribution Ten patients hospitalized with acute exacerbation of chronic bronchitis and purulent or mucopurulent sputum were admitted to the study. Patients with known or suspected allergy to penicillins and/or cephalosporins were excluded, as were those with hepatic or renal impairment. A tablet containing 875 mg of amoxicillin and 125 mg of potassium clavulanate (augmentin; Zambeletti S.p.a.) was administered at 8.00 a.m. after the patients had fasted overnight. Blood samples were taken before dosing and at 15 and 30 minutes, 1, 2, 4, 6, 8, 10 and 12 hours after administration. Sputum was collected by expectoration, after occlusion of the salivary ducts with cotton pads, at 30 minutes, 1, 2, 4, 6, 8, 10 and 12 hours after administration. Urine samples were collected immediately before and at 3, 6, 9 and 12 hours after administration. The volume of each sample was measured and two 10 ml aliquots retained for analysis. All samples were stored between - 40 and -70° C to ensure optimum stability. The conT ABLE 1 - Mean serum concentrations of amoxicillin and clavulanic acid in 10 patients with chronic bronchitis after a single oral dose of augmentin (875 mg amoxicillin and 125 mg potassium clavtl· lanate).
H ours after dosi ng 0.25
0.5
Amox icillin Mean ( ~gfml) 0.13
SD
4
0.32 1.06 11.23 4.4 0.1 0 0.17 0.4 1 2.6 1 1.19
Clavulanic acid Mean ( ~ gfml) 0. 13 0.53
SD
2
2.55 0. 10 0.13 0.54
8
6
1.23 0.37 0.30 0.13
1.1 5 0.28
ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20
Pharmacokinetics and Tissue Distribution of Amoxicillin plus Clavulanic Acid after Oral Administration in Man F. Fraschini, F. Scaglione, M. Falchi, S. Dugnani, M. Mezzetti, F. Cicchetti, G. Alfano & G.P. Pintucci To cite this article: F. Fraschini, F. Scaglione, M. Falchi, S. Dugnani, M. Mezzetti, F. Cicchetti, G. Alfano & G.P. Pintucci (1990) Pharmacokinetics and Tissue Distribution of Amoxicillin plus Clavulanic Acid after Oral Administration in Man, Journal of Chemotherapy, 2:3, 171-177, DOI: 10.1080/1120009X.1990.11739013 To link to this article: http://dx.doi.org/10.1080/1120009X.1990.11739013
Published online: 17 Jan 2017.
Submit your article to this journal
Article views: 1
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=yjoc20 Download by: [University of Toronto Libraries]
Date: 18 April 2017, At: 00:01
Journal of Chemotherapy
Pharmacokinetics and Tissue Distribution of Amoxicillin plus Clavulanic Acid after Oral Administration in Man F. FRASCHINI * - F. SCAGLIONE * M. FALCHI * - S. DUGNANI * M. MEZZETTI ** - F. CICCHETTI *** G. ALFANO *** - G.P. PINTUCCI **** Summary ---------------------------------Augmentin (875 amoxicillin and 125 mg potassium clavulanate) was administered orally to patients with chronic bronchitis. Concentrations of amoxicillin and clavulanic acid were measured in serum, sputum and urine . P eak serum levels for amoxicillin of 11.23 ± 2.61 f!g/ml were observed at 2 hours and for clavulanic acid of 2.55 ± 0.54 Jlg/ml at 1 hour. After 9 hours, 50% of the amoxicillin and 39% of the clavulanic acid had been renally excreted. The peak sputum concentration of amoxicillin was 1.31 ± 0.42 Jlg/ml at 4 hours and of clavulanate was 0. 79 ± 0.23 Jlg/ml at 2 hours. Patients awaiting surgery received an oral dose of augmentin as above. Samples of lung, tonsil, middle ear mucosa and prostate were obtained and tissue concentrations of both compounds measured. Peak levels of amoxicillin ranged from 0. 87 Jlg/g (tonsil) to 2.56 Jlg/g (lung) and of clavulanic acid from 0.20 Jlg/g (prostate) to 0.56 Jlg/g (lung) between 3 and 4 hours aft er dosing. Key words: Amoxicillin, clavulanate, augmentin, pharmacokinetics.
* D epartment of Pharmacology, Chemotherapy and Toxicology, University of Milan, Italy. ** Di vision of Chest Surgery, Policlinico Hospital, Mi lan, Italy. *** Division of Urology, Bassini Hospital, Milan, Italy. **** E .N.T. Division, Hospital of Vimercate, Vimercate (Milan), Italy. Correspondence: Prof. Franco Fraschini, Chair of Chemotherapy, Department of Pharmacology, Via Vanvitetli 32, 20129 Milano, Italy. © Edizioni Ri viste Scientifiche · Firenze
Vol. 2 · n. 3 (171 -177) · 1990
INTRODUCTION
The availability of preparations characterized by low toxicity coupled with high intrinsic ac tivity and high resistance to inactivation by bacterial enzymes has enhanced current antibacterial therapy. Clavulanic acid 1 • 2 , itself structurally related to the penicillins, h as little intrinsic antibacterial activity. However, it behaves as a high affinity substrate for bacterial ~ -lactamases 3 • 4 and h as the ability to protect ~ -l actam antibiotics from enzymic destruction. Thus the use of clavulanic acid in combination preparations has increased the potential therapeutic value of penicillins against ~ -lactamase producing organisms. Penicillins co-administered with a ~ - lacta mase inhibitor have been widely used to treat infections due to various pathogens. The most extensively investigated among these preparations is the combination of amoxicillin and clavulanic acid (augmentin) '· 6 , which may be administered either orally or intravenously . The serum pharmacokinetics of this combination have already been extensively investigated and the substantial kinetic compatibility of the two components has been confirmed 7 • 8 • In contrast, however, there are fewer studies on the distribution of amoxicillin and clavulanic acid in tissue compartments or in fluids other than blood 9 • 10 , particularly when given by the oral route. Therefore a multicenter study was set up to investigate distribution in tissues after oral administration of augmentin . Levels of both amoxicillin and clavulanic acid were determined in sputum and in lung, tonsil, prostate and middle ear mucosa . In addition, serum pharmaJSSN I t20-009X
172
F . FRASCHINI - F . SCAGLIO NE,
cokinetics and urinary excretion were determined to confirm existing work. We now present a full report of our earlier preliminary studies 11 • MATERIALS AND METHODS
The study was carried out in accordance with the Helsinki Declaration.
et aJii
centrations of amoxicillin and clavulanic acid in serum, sputum and urine were determined using the microbiological assay method described by Jackson et al. 12 • An image analysis system (BLC) was used to read inhibition zone areas and all assays were performed in triplicate. The pharmacokinetics of amoxicillin and clavulanic acid in serum and sputum were determined with a first-order, one-compartment open model, using a curve-fitting computer program.
Body fluid distribution Ten patients hospitalized with acute exacerbation of chronic bronchitis and purulent or mucopurulent sputum were admitted to the study. Patients with known or suspected allergy to penicillins and/or cephalosporins were excluded, as were those with hepatic or renal impairment. A tablet containing 875 mg of amoxicillin and 125 mg of potassium clavulanate (augmentin; Zambeletti S.p.a.) was administered at 8.00 a.m. after the patients had fasted overnight. Blood samples were taken before dosing and at 15 and 30 minutes, 1, 2, 4, 6, 8, 10 and 12 hours after administration. Sputum was collected by expectoration, after occlusion of the salivary ducts with cotton pads, at 30 minutes, 1, 2, 4, 6, 8, 10 and 12 hours after administration. Urine samples were collected immediately before and at 3, 6, 9 and 12 hours after administration. The volume of each sample was measured and two 10 ml aliquots retained for analysis. All samples were stored between - 40 and -70° C to ensure optimum stability. The conT ABLE 1 - Mean serum concentrations of amoxicillin and clavulanic acid in 10 patients with chronic bronchitis after a single oral dose of augmentin (875 mg amoxicillin and 125 mg potassium clavtl· lanate).
H ours after dosi ng 0.25
0.5
Amox icillin Mean ( ~gfml) 0.13
SD
4
0.32 1.06 11.23 4.4 0.1 0 0.17 0.4 1 2.6 1 1.19
Clavulanic acid Mean ( ~ gfml) 0. 13 0.53
SD
2
2.55 0. 10 0.13 0.54
8
6
1.23 0.37 0.30 0.13
1.1 5 0.28
