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David E Smith - One of the best experts on this subject based on the ideXlab platform.

  • Effect of transporter inhibition on the distribution of Cefadroxil in rat brain
    Fluids and Barriers of the CNS, 2014
    Co-Authors: Xiaomei Chen, Irena Loryan, Maryam Payan, Richard F Keep, David E Smith, Margareta Hammarlund-udenaes
    Abstract:

    Background Cefadroxil, a cephalosporin antibiotic, is a substrate for several membrane transporters including peptide transporter 2 (PEPT2), organic anion transporters (OATs), multidrug resistance-associated proteins (MRPs), and organic anion transporting polypeptides (OATPs). These transporters are expressed at the blood–brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB), and/or brain cells. The effect of these transporters on Cefadroxil distribution in brain is unknown, especially in the extracellular and intracellular fluids within brain. Methods Intracerebral microdialysis was used to measure unbound concentrations of Cefadroxil in rat blood, striatum extracellular fluid (ECF) and lateral ventricle cerebrospinal fluid (CSF). The distribution of Cefadroxil in brain was compared in the absence and presence of probenecid, an inhibitor of OATs, MRPs and OATPs, where both drugs were administered intravenously. The effect of PEPT2 inhibition by intracerebroventricular ( icv ) infusion of Ala-Ala, a substrate of PEPT2, on Cefadroxil levels in brain was also evaluated. In addition, using an in vitro brain slice method, the distribution of Cefadroxil in brain intracellular fluid (ICF) was studied in the absence and presence of transport inhibitors (probenecid for OATs, MRPs and OATPs; Ala-Ala and glycylsarcosine for PEPT2). Results The ratio of unbound Cefadroxil AUC in brain ECF to blood (K_p,uu,ECF) was ~2.5-fold greater during probenecid treatment. In contrast, the ratio of Cefadroxil AUC in CSF to blood (K_p,uu,CSF) did not change significantly during probenecid infusion. Icv infusion of Ala-Ala did not change Cefadroxil levels in brain ECF, CSF or blood. In the brain slice study, Ala-Ala and glycylsarcosine decreased the unbound volume of distribution of Cefadroxil in brain (V_u,brain), indicating a reduction in Cefadroxil accumulation in brain cells. In contrast, probenecid increased Cefadroxil accumulation in brain cells, as indicated by a greater value for V_u,brain. Conclusions Transporters (OATs, MRPs, and perhaps OATPs) that can be inhibited by probenecid play an important role in mediating the brain-to-blood efflux of Cefadroxil at the BBB. The uptake of Cefadroxil in brain cells involves both the influx transporter PEPT2 and efflux transporters (probenecid-inhibitable). These findings demonstrate that drug-drug interactions via relevant transporters may affect the distribution of cephalosporins in both brain ECF and ICF.

  • Relevance of PepT1 in the intestinal permeability and oral absorption of Cefadroxil.
    Pharmaceutical research, 2012
    Co-Authors: Maria M. Posada, David E Smith
    Abstract:

    To determine the contribution of intestinal PepT1 on the permeability and oral absorption of the β-lactam antibiotic drug Cefadroxil. The effective permeability (P eff ) of Cefadroxil was evaluated in wild-type and PepT1 knockout mice following in situ single-pass intestinal perfusions. The plasma concentration-time profiles of Cefadroxil were also examined after oral gavage. The P eff (cm/s) of Cefadroxil in wild-type mice was 0.49 × 10(-4) in duodenum, 0.80 × 10(-4) in jejunum, 0.88 × 10(-4) in ileum and 0.064 × 10(-4) in colon. The P eff (cm/s) in PepT1 knockout mice was significantly reduced in small intestine, but not in colon, as shown by values of 0.003 × 10(-4), 0.090 × 10(-4), 0.042 × 10(-4) and 0.032 × 10(-4), respectively. Jejunal uptake of Cefadroxil was saturable (Km = 2-4 mM) and significantly attenuated by the sodium-proton exchange inhibitor 5-(N,N-dimethyl)amiloride. Jejunal permeability of Cefadroxil was not affected by L-histidine, glycine, cephalothin, p-aminohippurate or N-methylnicotinamide. In contrast, Cefadroxil permeability was significantly reduced by glycylproline, glycylsarcosine, or cephalexin. Finally, PepT1 ablation resulted in 23-fold reductions in peak plasma concentrations and 14-fold reductions in systemic exposure of Cefadroxil after oral dosing. The findings are definitive in demonstrating that PepT1 is the major transporter responsible for the small intestinal permeability of Cefadroxil as well as its enhanced oral drug performance.

  • Impact of genetic knockout of PEPT2 on Cefadroxil pharmacokinetics, renal tubular reabsorption, and brain penetration in mice.
    Drug metabolism and disposition: the biological fate of chemicals, 2007
    Co-Authors: Hong Shen, Richard F Keep, Scott M. Ocheltree, David E Smith
    Abstract:

    The aim of this study was to examine the role of PEPT2, a proton-coupled oligopeptide transporter of the SLC15 family, on the disposition of the antibiotic Cefadroxil in the body, particularly the kidney and brain. Pharmacokinetic, tissue distribution, and renal clearance studies were performed in wild-type and PEPT2 null mice after intravenous bolus administration of [3H]Cefadroxil at 1, 12.5, 50, and 100 nmol/g body weight. Studies were also performed in the absence and presence of probenecid and quinine. Cefadroxil disposition kinetics was clearly nonlinear over the dose range studied (1–100 nmol/g), which was attributed to both saturable renal tubular secretion and reabsorption of the antibiotic. After an intravenous bolus dose of 1 nmol/g Cefadroxil, PEPT2 null mice exhibited a 3-fold greater total clearance and 3-fold lower systemic concentrations of drug compared with wild-type animals. Renal clearance studies further demonstrated that the renal reabsorption of Cefadroxil was almost completely abolished in PEPT2 null versus wild-type mice (3% versus 70%, p

  • mechanisms of Cefadroxil uptake in the choroid plexus studies in wild type and pept2 knockout mice
    Journal of Pharmacology and Experimental Therapeutics, 2004
    Co-Authors: Scott M. Ocheltree, Richard F Keep, Hong Shen, Jianming Xiang, David E Smith
    Abstract:

    The choroid plexus uptake of [ 3 H]Cefadroxil was studied in peptide transporter 2 (PEPT2) wild-type and null mice as a function of temperature, transport inhibitors, pH, and saturability. At normal pH (7.4) and temperature (37°C), the uptake of 1 μM Cefadroxil was reduced by 83% in PEPT2 –/– mice as compared with PEPT2 +/+ mice ( p p -aminohippurate ( p +/+ mice ( p –/– mice. Although a proton-stimulated uptake of Cefadroxil was demonstrated in PEPT2 +/+ mice (pH 6.5 versus pH 7.4; p –/– mice. Kinetic parameters for Cefadroxil (without p -aminohippurate) in wild-type mice were: V max = 5.4 pmol/mg/min, K m = 34 μM, and K d = 0.0069 μl/mg/min; in the presence of p -aminohippurate, the parameters were: V max = 4.1 pmol/mg/min, K m = 27 μM, and K d = 0.0064 μl/mg/min. In null animals, the kinetic parameters of Cefadroxil (without p -aminohippurate) were: V max = 2.7 pmol/mg/min, K m = 110 μM, and K d = 0.0084 μl/mg/min; in the presence of p -aminohippurate, only a K d = 0.010 μl/mg/min was observed. Based on kinetic and inhibitor analyses, it was determined that (under linear conditions), 80 to 85% of Cefadroxil9s uptake in choroid plexus is mediated by PEPT2, 10 to 15% by organic anion transporter(s), and 5% by nonspecific mechanisms. These findings demonstrate that PEPT2 is the primary transporter responsible for Cefadroxil uptake in the choroid plexus. Moreover, the data suggest a role for PEPT2 in the clearance of peptidomimetics from cerebrospinal fluid.

  • Mechanisms of Cefadroxil uptake in the choroid plexus: studies in wild-type and PEPT2 knockout mice.
    The Journal of pharmacology and experimental therapeutics, 2003
    Co-Authors: Scott M. Ocheltree, Richard F Keep, Hong Shen, Jianming Xiang, David E Smith
    Abstract:

    The choroid plexus uptake of [(3)H]Cefadroxil was studied in peptide transporter 2 (PEPT2) wild-type and null mice as a function of temperature, transport inhibitors, pH, and saturability. At normal pH (7.4) and temperature (37 degrees C), the uptake of 1 microM Cefadroxil was reduced by 83% in PEPT2(-/-) mice as compared with PEPT2(+/+) mice (p < 0.001). A further reduction was achieved in null animals by reducing the temperature to 4 degrees C, or by adding saturating concentrations of unlabeled Cefadroxil or p-aminohippurate (p < 0.05). Glycylsarcosine coadministration could inhibit the uptake of Cefadroxil in PEPT2(+/+) mice (p < 0.01) but not PEPT2(-/-) mice. Although a proton-stimulated uptake of Cefadroxil was demonstrated in PEPT2(+/+) mice (pH 6.5 versus pH 7.4; p < 0.01), no pH dependence was observed in PEPT2(-/-) mice. Kinetic parameters for Cefadroxil (without p-aminohippurate) in wild-type mice were: V(max) = 5.4 pmol/mg/min, K(m) = 34 microM, and K(d) = 0.0069 microl/mg/min; in the presence of p-aminohippurate, the parameters were: V(max) = 4.1 pmol/mg/min, K(m) = 27 microM, and K(d) = 0.0064 microl/mg/min. In null animals, the kinetic parameters of Cefadroxil (without p-aminohippurate) were: V(max) = 2.7 pmol/mg/min, K(m) = 110 microM, and K(d) = 0.0084 microl/mg/min; in the presence of p-aminohippurate, only a K(d) = 0.010 microl/mg/min was observed. Based on kinetic and inhibitor analyses, it was determined that (under linear conditions), 80 to 85% of Cefadroxil's uptake in choroid plexus is mediated by PEPT2, 10 to 15% by organic anion transporter(s), and 5% by nonspecific mechanisms. These findings demonstrate that PEPT2 is the primary transporter responsible for Cefadroxil uptake in the choroid plexus. Moreover, the data suggest a role for PEPT2 in the clearance of peptidomimetics from cerebrospinal fluid.

Milo Hilty - One of the best experts on this subject based on the ideXlab platform.

  • Linezolid versus Cefadroxil in the treatment of skin and skin structure infections in children.
    The Pediatric infectious disease journal, 2003
    Co-Authors: Kenneth Wible, Miguel Tregnaghi, Jon B. Bruss, Dona Fleishaker, Sharon Naberhuis-stehouwer, Milo Hilty
    Abstract:

    Background. Skin and skin structure infections are common reasons for visits to pediatricians, accounting for up to 18%. Staphylococcus aureus and Streptococcus pyogenes are the most frequently isolated Gram-positive pathogens in uncomplicated skin infections. Increasingly outpatient infections involve antibiotic-resistant Gram-positive pathogens including methicillin-resistant S. aureus. Methods. This randomized, blinded, comparator-controlled, multinational trial compared the efficacy and safety of linezolid and Cefadroxil for treatment of uncomplicated skin/skin structure infections in pediatric patients. Children ages 5 to 11 years were to receive linezolid suspension [10 mg/kg (up to 600 mg)] or Cefadroxil suspension [15 mg/kg (up to 500 mg)] every 12 h. Patients ages 12 to 17 years were to receive linezolid tablets (600 mg) or Cefadroxil capsules (500 mg) every 12 h. Therapy lasted 10 to 21 consecutive days with a follow-up visit 10 to 21 days post-therapy. Results. Linezolid and Cefadroxil were consistently effective treatments across all primary and secondary efficacy assessments. At follow-up cure rates were 88.7% (205 of 231) for linezolid-treated and 86.2% (193 of 224) for Cefadroxil-treated intent-to-treat patients; cure rates were 91.0% (201 of 221) for linezolid-treated and 90.0% (189 of 210) for Cefadroxil-treated clinically evaluable patients. S. aureus was eradicated in 89.6% (120 of 134) linezolid-treated and 88.8% (111 of 125) Cefadroxil-treated microbiologically evaluable patients. Gastrointestinal complaints were the most common adverse events reported, without significant differences between treatment groups, and myelosuppression was not observed in this study Conclusions. Linezolid is well-tolerated and as effective as Cefadroxil in treating uncomplicated skin infections in pediatric patients. Linezolid effectively treated infections caused by S. aureus, methicillin-resistant S. aureus and S. pyogenes.

Novicki Dc - One of the best experts on this subject based on the ideXlab platform.

  • Cefadroxil in skin and skin-structure foot infections: a retrospective review.
    Advances in Therapy, 1995
    Co-Authors: Yu Gv, Novicki Dc
    Abstract:

    The efficacy and safety of Cefadroxil in eradicating localized skin and skin-structure infections of the foot were investigated in a retrospective chart review of 222 consecutive patients from two private practices seen over a 10-year period. Of the 189 patients for whom follow-up data were available, 187 (99%) received Cefadroxil 500 mg twice daily, and 2 patients (1%) received 250 mg twice daily. The duration of therapy was 2 weeks or less in 87% of patients, with a median duration of therapy of 11.4 days (range, 5 to 35 days). Of the 189 clinically evaluable patients, 179 (95%) achieved a favorable clinical response to treatment; of the 57 patients with microbiologic cultures, 54 (95%) experienced a satisfactory bacteriologic response to therapy; no adverse events related to Cefadroxil therapy were identified during the review. The overall results from this retrospective study suggest that Cefadroxil is an effective agent with a favorable safety profile for the treatment of skin and skin-structure infections of the foot.

Kenneth Wible - One of the best experts on this subject based on the ideXlab platform.

  • Linezolid versus Cefadroxil in the treatment of skin and skin structure infections in children.
    The Pediatric infectious disease journal, 2003
    Co-Authors: Kenneth Wible, Miguel Tregnaghi, Jon B. Bruss, Dona Fleishaker, Sharon Naberhuis-stehouwer, Milo Hilty
    Abstract:

    Background. Skin and skin structure infections are common reasons for visits to pediatricians, accounting for up to 18%. Staphylococcus aureus and Streptococcus pyogenes are the most frequently isolated Gram-positive pathogens in uncomplicated skin infections. Increasingly outpatient infections involve antibiotic-resistant Gram-positive pathogens including methicillin-resistant S. aureus. Methods. This randomized, blinded, comparator-controlled, multinational trial compared the efficacy and safety of linezolid and Cefadroxil for treatment of uncomplicated skin/skin structure infections in pediatric patients. Children ages 5 to 11 years were to receive linezolid suspension [10 mg/kg (up to 600 mg)] or Cefadroxil suspension [15 mg/kg (up to 500 mg)] every 12 h. Patients ages 12 to 17 years were to receive linezolid tablets (600 mg) or Cefadroxil capsules (500 mg) every 12 h. Therapy lasted 10 to 21 consecutive days with a follow-up visit 10 to 21 days post-therapy. Results. Linezolid and Cefadroxil were consistently effective treatments across all primary and secondary efficacy assessments. At follow-up cure rates were 88.7% (205 of 231) for linezolid-treated and 86.2% (193 of 224) for Cefadroxil-treated intent-to-treat patients; cure rates were 91.0% (201 of 221) for linezolid-treated and 90.0% (189 of 210) for Cefadroxil-treated clinically evaluable patients. S. aureus was eradicated in 89.6% (120 of 134) linezolid-treated and 88.8% (111 of 125) Cefadroxil-treated microbiologically evaluable patients. Gastrointestinal complaints were the most common adverse events reported, without significant differences between treatment groups, and myelosuppression was not observed in this study Conclusions. Linezolid is well-tolerated and as effective as Cefadroxil in treating uncomplicated skin infections in pediatric patients. Linezolid effectively treated infections caused by S. aureus, methicillin-resistant S. aureus and S. pyogenes.

Richard F Keep - One of the best experts on this subject based on the ideXlab platform.

  • Influence of peptide transporter 2 (PEPT2) on the distribution of Cefadroxil in mouse brain: A microdialysis study.
    Biochemical pharmacology, 2017
    Co-Authors: Xiaomei Chen, Margareta Hammarlund-udenaes, Richard F Keep, Yan Liang, Hao Jie Zhu, David C. Smith
    Abstract:

    Peptide transporter 2 (PEPT2) is a high-affinity low-capacity transporter belonging to the proton-coupled oligopeptide transporter family. Although many aspects of PEPT2 structure-function are known, including its localization in choroid plexus and neurons, its regional activity in brain, especially extracellular fluid (ECF), is uncertain. In this study, the pharmacokinetics and regional brain distribution of Cefadroxil, a β-lactam antibiotic and PEPT2 substrate, were investigated in wildtype and Pept2 null mice using in vivo intracerebral microdialysis. Cefadroxil was infused intravenously over 4h at 0.15mg/min/kg, and samples obtained from plasma, brain ECF, cerebrospinal fluid (CSF) and brain tissue. A permeability-surface area experiment was also performed in which 0.15mg/min/kg Cefadroxil was infused intravenously for 10min, and samples obtained from plasma and brain tissues. Our results showed that PEPT2 ablation significantly increased the brain ECF and CSF levels of Cefadroxil (2- to 2.5-fold). In contrast, there were no significant differences between wildtype and Pept2 null mice in the amount of Cefadroxil in brain cells. The unbound volume of distribution of Cefadroxil in brain was 60% lower in Pept2 null mice indicating an uptake function for PEPT2 in brain cells. Finally, PEPT2 did not affect the influx clearance of Cefadroxil, thereby, ruling out differences between the two genotypes in drug entry across the blood-brain barriers. These findings demonstrate, for the first time, the impact of PEPT2 on brain ECF as well as the known role of PEPT2 in removing peptide-like drugs, such as Cefadroxil, from the CSF to blood.

  • Effect of transporter inhibition on the distribution of Cefadroxil in rat brain
    Fluids and Barriers of the CNS, 2014
    Co-Authors: Xiaomei Chen, Irena Loryan, Maryam Payan, Richard F Keep, David E Smith, Margareta Hammarlund-udenaes
    Abstract:

    Background Cefadroxil, a cephalosporin antibiotic, is a substrate for several membrane transporters including peptide transporter 2 (PEPT2), organic anion transporters (OATs), multidrug resistance-associated proteins (MRPs), and organic anion transporting polypeptides (OATPs). These transporters are expressed at the blood–brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB), and/or brain cells. The effect of these transporters on Cefadroxil distribution in brain is unknown, especially in the extracellular and intracellular fluids within brain. Methods Intracerebral microdialysis was used to measure unbound concentrations of Cefadroxil in rat blood, striatum extracellular fluid (ECF) and lateral ventricle cerebrospinal fluid (CSF). The distribution of Cefadroxil in brain was compared in the absence and presence of probenecid, an inhibitor of OATs, MRPs and OATPs, where both drugs were administered intravenously. The effect of PEPT2 inhibition by intracerebroventricular ( icv ) infusion of Ala-Ala, a substrate of PEPT2, on Cefadroxil levels in brain was also evaluated. In addition, using an in vitro brain slice method, the distribution of Cefadroxil in brain intracellular fluid (ICF) was studied in the absence and presence of transport inhibitors (probenecid for OATs, MRPs and OATPs; Ala-Ala and glycylsarcosine for PEPT2). Results The ratio of unbound Cefadroxil AUC in brain ECF to blood (K_p,uu,ECF) was ~2.5-fold greater during probenecid treatment. In contrast, the ratio of Cefadroxil AUC in CSF to blood (K_p,uu,CSF) did not change significantly during probenecid infusion. Icv infusion of Ala-Ala did not change Cefadroxil levels in brain ECF, CSF or blood. In the brain slice study, Ala-Ala and glycylsarcosine decreased the unbound volume of distribution of Cefadroxil in brain (V_u,brain), indicating a reduction in Cefadroxil accumulation in brain cells. In contrast, probenecid increased Cefadroxil accumulation in brain cells, as indicated by a greater value for V_u,brain. Conclusions Transporters (OATs, MRPs, and perhaps OATPs) that can be inhibited by probenecid play an important role in mediating the brain-to-blood efflux of Cefadroxil at the BBB. The uptake of Cefadroxil in brain cells involves both the influx transporter PEPT2 and efflux transporters (probenecid-inhibitable). These findings demonstrate that drug-drug interactions via relevant transporters may affect the distribution of cephalosporins in both brain ECF and ICF.

  • Effect of transporter inhibition on the distribution of Cefadroxil in rat brain
    Fluids and barriers of the CNS, 2014
    Co-Authors: Xiaomei Chen, Irena Loryan, Maryam Payan, Richard F Keep, David C. Smith, Margareta Hammarlund-udenaes
    Abstract:

    Cefadroxil, a cephalosporin antibiotic, is a substrate for several membrane transporters including peptide transporter 2 (PEPT2), organic anion transporters (OATs), multidrug resistance-associated proteins (MRPs), and organic anion transporting polypeptides (OATPs). These transporters are expressed at the blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB), and/or brain cells. The effect of these transporters on Cefadroxil distribution in brain is unknown, especially in the extracellular and intracellular fluids within brain. Intracerebral microdialysis was used to measure unbound concentrations of Cefadroxil in rat blood, striatum extracellular fluid (ECF) and lateral ventricle cerebrospinal fluid (CSF). The distribution of Cefadroxil in brain was compared in the absence and presence of probenecid, an inhibitor of OATs, MRPs and OATPs, where both drugs were administered intravenously. The effect of PEPT2 inhibition by intracerebroventricular (icv) infusion of Ala-Ala, a substrate of PEPT2, on Cefadroxil levels in brain was also evaluated. In addition, using an in vitro brain slice method, the distribution of Cefadroxil in brain intracellular fluid (ICF) was studied in the absence and presence of transport inhibitors (probenecid for OATs, MRPs and OATPs; Ala-Ala and glycylsarcosine for PEPT2). The ratio of unbound Cefadroxil AUC in brain ECF to blood (Kp,uu,ECF) was ~2.5-fold greater during probenecid treatment. In contrast, the ratio of Cefadroxil AUC in CSF to blood (Kp,uu,CSF) did not change significantly during probenecid infusion. Icv infusion of Ala-Ala did not change Cefadroxil levels in brain ECF, CSF or blood. In the brain slice study, Ala-Ala and glycylsarcosine decreased the unbound volume of distribution of Cefadroxil in brain (Vu,brain), indicating a reduction in Cefadroxil accumulation in brain cells. In contrast, probenecid increased Cefadroxil accumulation in brain cells, as indicated by a greater value for Vu,brain. Transporters (OATs, MRPs, and perhaps OATPs) that can be inhibited by probenecid play an important role in mediating the brain-to-blood efflux of Cefadroxil at the BBB. The uptake of Cefadroxil in brain cells involves both the influx transporter PEPT2 and efflux transporters (probenecid-inhibitable). These findings demonstrate that drug-drug interactions via relevant transporters may affect the distribution of cephalosporins in both brain ECF and ICF.

  • Impact of Lipopolysaccharide-Induced Inflammation on the Disposition of the Aminocephalosporin Cefadroxil
    Antimicrobial agents and chemotherapy, 2013
    Co-Authors: Yeamin Huh, Richard F Keep, David C. Smith
    Abstract:

    ABSTRACT The purpose of this study was to determine if the disposition of Cefadroxil, an α-amino-containing β-lactam antibiotic, changes during lipopolysaccharide (LPS)-induced acute inflammation. Six hours after LPS or saline treatment, mice received 1 nmol/g Cefadroxil intravenously along with inulin for glomerular filtration rate (GFR) determination. Serial blood samples, along with tissue and urine samples, were collected at predetermined time points. In order to determine inflammation-induced changes in GFR, renal tubular secretion, and reabsorption, it was necessary to coadminister 70 mg/kg probenecid. Changes in the expression of the mRNA of transporters involved in Cefadroxil disposition in the kidneys and choroid plexus were also investigated 6 h after LPS treatment. The results demonstrated marked increases in blood, cerebrospinal fluid, and tissue Cefadroxil concentrations with LPS treatment. Tissue-to-blood concentration ratios were decreased by 4.6-fold in the choroid plexus and by 2.5-fold in the kidneys during LPS-induced inflammation. Renal, but not choroid plexus, mRNA expression of peptide transporter 2, organic-anion transporter 1 (OAT1), OAT3, and multidrug resistance-associated protein 4 was mildly reduced in LPS-treated mice. The renal clearance of Cefadroxil was substantially decreased by LPS treatment (3-fold). GFR was also reduced by 3-fold in LPS-treated mice, but no significant differences in the fractional reabsorption of Cefadroxil and renal secretion once normalized by GFR were observed. These findings demonstrated that LPS-induced inflammation has a dramatic effect on the renal excretion of Cefadroxil. It appears that changes in transporter expression played a minor role during LPS treatment but that renal dysfunction, associated with GFR reduction, was responsible for the substantial increase in plasma Cefadroxil concentration-time profiles.

  • Impact of genetic knockout of PEPT2 on Cefadroxil pharmacokinetics, renal tubular reabsorption, and brain penetration in mice.
    Drug metabolism and disposition: the biological fate of chemicals, 2007
    Co-Authors: Hong Shen, Richard F Keep, Scott M. Ocheltree, David E Smith
    Abstract:

    The aim of this study was to examine the role of PEPT2, a proton-coupled oligopeptide transporter of the SLC15 family, on the disposition of the antibiotic Cefadroxil in the body, particularly the kidney and brain. Pharmacokinetic, tissue distribution, and renal clearance studies were performed in wild-type and PEPT2 null mice after intravenous bolus administration of [3H]Cefadroxil at 1, 12.5, 50, and 100 nmol/g body weight. Studies were also performed in the absence and presence of probenecid and quinine. Cefadroxil disposition kinetics was clearly nonlinear over the dose range studied (1–100 nmol/g), which was attributed to both saturable renal tubular secretion and reabsorption of the antibiotic. After an intravenous bolus dose of 1 nmol/g Cefadroxil, PEPT2 null mice exhibited a 3-fold greater total clearance and 3-fold lower systemic concentrations of drug compared with wild-type animals. Renal clearance studies further demonstrated that the renal reabsorption of Cefadroxil was almost completely abolished in PEPT2 null versus wild-type mice (3% versus 70%, p