Pharmacokinetics Of Cefadroxil Research Articles

Species differences in the pharmacokinetics of cefadroxil as determined in wildtype and humanized PepT1 mice

PepT1 (SLC15A1) is a high-capacity low-affinity transporter that is important in the absorption of digested di/tripeptides from dietary protein in the small intestine. PepT1 is also crucial for the intestinal uptake and absorption of therapeutic agents such as the β-lactam aminocephalosporins and antiviral prodrugs. Species differences, however, have been observed in PepT1-mediated intestinal absorption and pharmacokinetics, thereby, making it more difficult to predict systemic drug exposure. In the present study, we evaluated the in situ intestinal permeability of the PepT1 substrate cefadroxil in wildtype and humanized PepT1 (huPepT1) mice, and the in vivo absorption and disposition of drug after escalating oral doses. The in situ perfusions indicated that cefadroxil had a twofold higher affinity (i.e., twofold lower Km) for jejunal PepT1 in huPepT1 mice, lower but substantial permeability in all regions of the small intestine, and low but measureable permeability in the colon as compared to wildtype animals. The in vivo experiments indicated almost superimposable pharmacokinetic profiles between the two genotypes after intravenous bolus dosing of cefadroxil. In contrast, after oral dose escalation, the systemic exposure of cefadroxil was reduced in huPepT1 mice as compared to wildtype animals. Moreover, the AUC and Cmax versus dose relationships were nonlinear for huPepT1 but not wildtype mice, and similar to that observed from human subjects. In conclusion, our findings indicate that huPepT1 mice may provide a valuable tool in the drug discovery process by better predicting the oral pharmacokinetic profiles of PepT1 substrates in humans.

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

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. The absorption and disposition kinetics of [3H]cefadroxil were 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 were also determined in both genotypes after 44.5 nmol/g intravenous bolus doses. 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 were 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. 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.

The pharmacokinetics of cefadroxil in the foal.

The pharmacokinetics of cefadroxil in the foal.

Pharmacokinetics of cefadroxil and cefaclor during an eight-day dosage period.

The concentrations of cefadroxil and cefaclor in serum were studied in eight healthy volunteers receiving 1,000 mg of both substances three times per day for 8 days. Intraindividual comparisons showed an increase in peak serum levels of cefadroxil from days 1 to 8 in seven of eight volunteers. Cefaclor peak concentrations did not rise during the 8 days.

Pharmacokinetics of cefadroxil in patients with impaired renal function.

Pharmacokinetics of cefadroxil in patients with impaired renal function.

Pharmacokinetics of cefadroxil in patients with terminal renal impairment

The pharmacokinetics of cefadroxil were studied in 15 subjects divided into 3 groups: healthy volunteers, patients with terminal renal impairment in interdialysis sessions and patients with terminal renal impairment undergoing hemodialysis sessions. The serum levels of the antibiotic were determined by a microbiologic plate diffusion method using Bacillus subtilis (ATCC no. 6633) as the test organism. Renal impairment causes a decrease in the elimination rate of the antibiotic. The serum half-life has a value of 1.20 ± 0.21 h in the healthy volunteers, 26.56 ± 8.00h in patients in interdialysis periods and 2.45 ± 0.72 h in patients undergoing hemodialysis sessions. Hemodialysis partially restores absorption and elimination of cefadroxil to levels which approach those established in healthy volunteers.

Pharmacokinetics of cefadroxil in normal subjects and in patients with renal insufficiency

Pharmacokinetics of cefadroxil, a new oral semisynthetic cephalosporin, was studied in 5 subjects with normal renal function and in 20 patients with varying degrees of renal insufficiency. All subjects received 1,000 mgper os in single dose and the elimination phase was studied. In healthy subjects, elimination half-life (T1/2) was 1.39 ± 0.06 h. Apparent volume of distribution was 0.305 liters/kg and area under the serum concentration versus time curve AUC was 82.94 ± 19.98 µg · h/ml. Peak level averaged 25.72 ± 4.68 µg · ml−1 and occurred at 1.20 ± 0.45 h postingestion. 93.0 ± 3.6% of the dose was recovered in urine during the first 24 h. Renal and serum clearance averaged 166.7 and 172.4 ml · min−1/1.73 m2, respectively. In patients with renal insufficiency, T1/2 increased to 25.49 h in severe chronic renal failure. Renal impairment did not significantly modify volume of distribution. During a 6-to 8-hour hemodialysis session, antibiotic serum concentrations decreased by 75.4 ± 5.6%. Dosage schedules could be suggested on the basis of these pharmacokinetic results.

Influence of dose on the pharmacokinetics of cefadroxil.

The pharmacokinetics of Cefadroxil have been studied in a crossover study involving 20 experiments in four healthy volunteers (19--24 years), after oral administration of five individual doses of 250, 500, 750, 1000 and 1500 mg of the antibiotic in capsules to each person. Plasma and urine concentrations of the antibiotic were determined microbiologically by a plate diffusion method. The antibiotic followed an open, single-compartment kinetic model. The plasma half-life was not significantly influenced by dose; the average was 1.438 +/- 0.220 h. The percentage of the antibiotic excreted in urine, too, was not significantly affected by the dose, being close to 80% of the quantity originally administered within 24 h. The values of Cmax and (AUC) increased linearly with the administered dose.

Pharmacokinetics of Cefadroxil in Normal Subjects and in Patients with Renal Insufficiency

Pharmacokinetics of cefadroxil, a new orally semisynthetic cephalosporin, was studied in 5 subjects with normal renal function and in 20 patients with varying degrees of renal insufficiency. All subjects received 1,000 mg per os in a single dose and the elimination phase was studied. In healthy subjects, elimination half-life (T1/2) was 1.39 +/- 0.06 h. Apparent volume of distribution was 0.305 liters/kg and area under the serum concentration versus time curve AUC was 82.94 +/- 19.98 microgram . h/ml. Peak level averaged 25.72 +/- 4.68 microgram . ml-1 and occurred at 1.20 +/- 0.45 h postingestion. 93.0 +/- 3.6% of the dose was recovered in urine during the first 24 h. Renal and serum clearance averaged 166.7 and 172.4 ml . min-1/1.73 m2, respectively. In patients with renal insufficiency, T1/2 increased to 25.49 h in severe chronic renal failure. Renal impairment did not significantly modify volume of distribution. During a 6- to 8-hour hemodialysis session, antibiotic serum concentrations decreased by 75.4 +/- 5.6%. Dosage schedules could be suggested on the basis of these pharmacokinetic results.

Absorption, excretion and pharmacokinetics of cefadroxil in human

Absorption, excretion and pharmacokinetics of cefadroxil in human