Intestinal absorption mechanism of amphoteric β-lactam antibiotics I: Comparative absorption and evidence for saturable transport of amino-β-iactam antibiotics by in situ rat small intestine

Tsuji, Akira; Nakashima, Emi; Kagami, Izumi; Yamana, Tsukinaka

doi:10.1002/jps.2600700714

Cited by 70 publications

(2 citation statements)

References 29 publications

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“…This antibiotic is almost completely absorbed from the gastrointestinal tract, is not metabolized, and is excreted in the urine unchanged by renal glomerular filtration, active tubular secretion, and active tubular reabsorption ( 10 , 11 ). Having low lipid solubility, and being completely ionized in the gastrointestinal tract, the absorption of cefadroxil (and other aminocephalosporin antibiotics) was considered to occur by some “specialized” transport mechanism ( 12 ). With the advent of molecular cloning, we now realize that the intestinal absorption of cefadroxil is a coordinated process in which cellular uptake from the lumen occurs via PepT1 and cellular efflux into the blood occurs, in part, via the ATP-binding cassette (ABC) transporters Mrp3 (Abcc3) and Mrp4 (Abcc4) ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…[1][2][3] These absorbable peptides composed of two or three amino acids exhibit a variety of structures, charges, and hydrophilicities because the 20 constituent amino acids can undergo extensive combinations to form 400 dipeptides and 8000 tripeptides. 4,5) Therefore, hPEPT1 exhibits a broad substrate specificity ranging from peptides to peptidomimetic therapeutic drugs such as beta-lactams, [6][7][8][9][10] angiotensin converting enzyme inhibitor 1,11) and antiviral prodrugs. [12][13][14] hPEPT1 effectively absorbs the therapeutic prodrugs and facilitates enhancement of bioavailability.…”

Section: Introductionmentioning

confidence: 99%

Protonation State of a Histidine Residue in Human Oligopeptide Transporter 1 (hPEPT1) Regulates hPEPT1-Mediated Efflux Activity

Omori

Fujisawa

Sasaki

et al. 2021

Biological & Pharmaceutical Bulletin

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To clarify the role of an amino acid residue in the pH-dependent efflux process in Chinese hamster ovary (CHO) cells expressing the human oligopeptide transporter hPEPT1 (CHO/hPEPT1), we determined the effect of extracellular pH on the hPEPT1-mediated efflux process. The efflux of glycylsarcosine (Gly-Sar), a typical substrate for hPEPT1, was determined using an infinite dilution method after cells were preloaded with [ 3 H]-Gly-Sar. The efflux of [ 3 H]-Gly-Sar was stimulated by 5 mM unlabeled hPEPT1 substrates in the medium. This trans-stimulation phenomenon showed that hPEPT1 mediated the efflux of [ 3 H]-Gly-Sar from CHO/hPEPT1 and that hPEPT1 is a bi-directional transporter. We then determined the effect of extracellular pH (varying from 8.0 to 3.5) on the efflux activity. The efflux activity by hPEPT1 decreased with the decrease in extracellular pH. The Henderson-Hasselbälch-type equation, which fitted well to the pH-profile of efflux activity, indicated that a single amino acid residue with a pK a value of approximately 5.7 regulates the efflux activity. The pH-profile of the efflux activity remained almost unchanged irrespective of the proton gradient across the plasma membrane. In addition, the chemical modification of the histidine residue with diethylpyrocarbonate completely abolished the efflux activity from cells, which could be prevented by the presence of 10 mM Gly-Sar. These data indicate that the efflux process of hPEPT1 is also regulated in a pHdependent manner by the protonation state of a histidine residue located at or near the substrate recognition site facing the extracellular space.

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Evidence of a specialized transport mechanism for the intestinal absorption of baclofen

Merino

Peris-Ribera

Torres‐Molina

et al. 1989

Biopharm & Drug Disp

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Absorption of the spasmolytic drug baclofen in three selected intestinal segments of living anaesthetized rats in situ, is shown to be a specialized transport mechanism obeying Michaelis-Menten kinetics. Equation parameters were calculated through different procedures, whose features are discussed. A computer method based on the integrated form of Michaelis-Menten equation which reproduces the entire time course of drug absorption from the data found in three intestinal perfusion series at different initial concentrations, yielded Vm and Km values of 12.0 mg h-1 and 8.0 mg, respectively, in the mean segment of the small intestine, a rather selective absorption site for baclofen. Lesser but comparable absorption rates were found in the proximal and distal segments of the small intestine, whereas in colon, drug absorption was negligible. Baclofen transport was significantly reduced in the presence of the enzymatic inhibitor sodium azide. If these results were extrapolated to humans, they would explain the excellent bioavailability profiles reported for baclofen at normal doses in spite of its physicochemical properties, which do not favour passive diffusion. Based on the same principle, the administration of usual doses at shorter time intervals could be recommended, instead of high, when higher plasma levels at steady-state are needed. On the other hand, more than 8-h sustained-release preparations of baclofen should, probably, be avoided.

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Intestinal absorption mechanism of amphoteric β-lactam antibiotics I: Comparative absorption and evidence for saturable transport of amino-β-iactam antibiotics by in situ rat small intestine

Cited by 70 publications

References 29 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

Protonation State of a Histidine Residue in Human Oligopeptide Transporter 1 (hPEPT1) Regulates hPEPT1-Mediated Efflux Activity

Evidence of a specialized transport mechanism for the intestinal absorption of baclofen

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