Pharmacokinetics of cefadroxil after oral administration in humans

Rosa, Francesco La; Ripa, Sandro; Prenna, Manuela; Ghezzi, A.; Pfeffer, Morris

doi:10.1128/aac.21.2.320

Cited by 23 publications

(14 citation statements)

References 7 publications

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“…The linear oral absorption profile of cefadroxil demonstrated a lack of intestinal PepT1 saturation that was also consistent with a dose escalation study of glycylsarcosine in wild-type and PepT1 knockout mice ( 27 ). It should be appreciated that the oral doses of cefadroxil administered to mice (i.e., 44.5 to 356 nmol/g) were representative of the doses used clinically in 70 kg patients (i.e., 0.125 to 1.0 g) and resulted in peak plasma concentrations of 37 to 300 μM in wild-type animals, values also observed in humans ( 10 , 21 , 28 ). Given a stomach fluid volume of 0.4 mL (29), a 20 g mouse would have small intestinal concentrations approximating 18 mM, values in excess of cefadroxil's Km of 2-4 mM as determined by in situ jejunal perfusions in wild-type mice (23).…”

Section: Discussionmentioning

confidence: 92%

In Vivo Absorption and Disposition of Cefadroxil After Escalating Oral Doses in Wild-Type and PepT1 Knockout Mice

Posada

Smith

2013

Pharm Res

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Purpose To determine the effect of PepT1 on the absorption and disposition of cefadroxil, including the potential for saturable intestinal uptake, after escalating oral doses of drug. Methods The absorption and disposition kinetics of [3H]cefadroxil was determined in wild-type and PepT1 knockout mice after 44.5, 89.1, 178, and 356 nmol/g oral doses of drug. The pharmacokinetics of [3H]cefadroxil was also determined in both genotypes after 44.5 nmol/g intravenous bolus doses. Results PepT1 deletion reduced the area under the plasma concentration-time profile (AUC0-120) of cefadroxil by 10-fold, the maximum plasma concentration (Cmax) by 17.5-fold, and increased the time to reach a maximum plasma concentration (Tmax) by 3-fold. There was no evidence of nonlinear intestinal absorption since AUC0-120 and Cmax values changed in a dose-proportional manner. Moreover, the pharmacokinetics of cefadroxil was not different between genotypes after intravenous bolus doses, indicating that PepT1 did not affect drug disposition. Finally, no differences were observed in the peripheral tissue distribution of cefadroxil (i.e., outside gastrointestinal tract) once these tissues were corrected for differences in perfusing blood concentrations. Conclusions The findings demonstrate convincingly the critical role of intestinal PepT1 in both the rate and extent of oral administration for cefadroxil and potentially other aminocephalosporin drugs.

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Section: Discussionmentioning

confidence: 92%

In Vivo Absorption and Disposition of Cefadroxil After Escalating Oral Doses in Wild-Type and PepT1 Knockout Mice

Posada

Smith

2013

Pharm Res

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“…In comparison with older orally administered cephalosporins, cefprozil has a position between cefaclor and cefadroxil in terms of its absorption characteristics (7,15,24,29,38,42), with a low invasion rate like that of cefadroxil and with a high maximal concentration in serum and fast elimination phase similar to those of cefaclor. With cefadroxil, we found a slight increase in the peak concentrations in serum during an 8-day dosage period with three doses of 1,000 mg per day orally in volunteers, which could not be seen with cefprozil, 500 mg b.i.d.…”

Section: Resultsmentioning

confidence: 99%

Multiple-dose pharmacokinetics of cefprozil and its impact on intestinal flora of volunteers

Lode

Müller

Börner

et al. 1992

Antimicrob Agents Chemother

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The pharmacokinetics of cefprozil were determined with 12 volunteers (8 received cefprozil and 4 received a placebo) after oral administration of 500 mg every 12 h over an 8-day period in a randomized, double-blind, placebo-controlled design. Concentrations in serum and urine were measured by high-pressure liquid chromatography and bioassay. The pharmacokinetic parameters were calculated on the basis of an open one-compartment model. The mean maximum concentration in serum on day 1 was 11.5 ± 2.6 mg/liter, and the time to reach maximum concentration was 122.3 ± 30 min after administration. Bioavailability parameters (area under the concentration-time curve from zero to infinity, maximum concentration of the drug in serum, and urinary recovery) indicated an excellent absorption. No accumulation over the 8-day period was registered. Cefprozil had a short biological elimination half-life of 58 ± 10 min and a renal clearance of 210 ± 51 ml/min, indicating high rates of renal excretion and tubular secretion. Analysis of the fecal flora showed an ecological impact of cefprozil on the intestinal microflora, such as a moderate decrease in enterobacteria and a slight increase in enterococci, staphylococci, and bacteroides during the study. The number of all bacterial species was already normalized 4 days after the administration period. The tolerance of cefprozil proved to be excellent; only a slight and reversible increase of liver enzymes (in two volunteers), mild cephalalgia, tiredness, and soft stool were registered during the 8-day period. Cefprozil had excellent absorption, no accumulation over an 8-day period, and only a limited impact on the intestinal microflora.Cefprozil (BMY-28100) is a new oral cephalosporin antibiotic with improved antimicrobial activity and efficacy against a broad spectrum of gram-positive and gram-negative pathogens (6,8,15,20,37). The objectives of our trial were to determine the pharmacokinetic properties of cefprozil after single and multiple dosing, to determine the effect on the intestinal flora in volunteers, and to assess the tolerance of cefprozil over an 8-day application period.(Part of this paper was presented previously [28a].) MATERIALS AND METHODSStudy design. The study was based on a randomized, double-blind, placebo-controlled, multiple-dose design. The protocol was approved by the local ethics committee.Volunteers. Twelve healthy test subjects (six females and six males) participated in the study. Eight of them received cefprozil, and four (two females and two males) took placebos. Mean (+ standard deviation) age (24 ± 2 years), body weight (65 ± 9 kg), body surface (1.78 m2 + 0.18), and creatinine clearance (108 + 23 ml/min/1.73 m2) showed no differences between placebo-and antibiotic-treated volunteers. The volunteers were healthy according to medical histories, physical examinations, hematologic tests, clinical chemistries, and urinalyses. These parameters were examined several times before, during, and after the study and showed no pathological alterations. All subjec...

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“…Because of slower renal excretion, cefadroxil persists in the circulation for 1.5 times as long as cephalexin (90 versus 60 min) (11). The prolonged half-life permits oral administration every 12 h, compared to every 6 h for cephalexin, a considerable advantage for outpatient treatment in which compliance may be less than ideal.…”

Section: Resultsmentioning

confidence: 99%

Comparison of cefadroxil and cephalexin in the treatment of community-acquired pneumonia

Blaser¹,

Klaus²,

Jacobson³

et al. 1983

Antimicrob Agents Chemother

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Thirty-four patients with community-acquired acute pneumonias were treated in a prospective, randomized trial with either cefadroxil, 500 mg twice daily, or cephalexin, 250 mg four times daily. In both groups of patients, the presence of chronic illnesses predisposing to pneumonia was common. Streptococcus pneumoniae was isolated from 65% of the initial sputum specimens, and most illnesses were of mild to moderate severity. All 19 cases treated with cefadroxil and all 15 cases treated with cephalexin were clinically cured, and adverse reactions to the medications were minimal. The success of these regimens suggests that outpatient use of oral cephalosporin therapy may be an appropriate treatment of patients with mild or moderate community-acquired pneumonia.

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Pharmacokinetics of cefadroxil after oral administration in humans

Cited by 23 publications

References 7 publications

In Vivo Absorption and Disposition of Cefadroxil After Escalating Oral Doses in Wild-Type and PepT1 Knockout Mice

In Vivo Absorption and Disposition of Cefadroxil After Escalating Oral Doses in Wild-Type and PepT1 Knockout Mice

Multiple-dose pharmacokinetics of cefprozil and its impact on intestinal flora of volunteers

Comparison of cefadroxil and cephalexin in the treatment of community-acquired pneumonia

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