Characterization of the Oral Absorption of β-Lactam Antibiotics II: Competitive Absorption and Peptide Carrier Specificity

Sinko, Patrick J.; Amidon, Gordon L.

doi:10.1002/jps.2600780904

Cited by 50 publications

(18 citation statements)

References 13 publications

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“…Km value for CEX, 3.6 mM, was compatible with those determined by the experiment with rat small intestine in vivo. 14) However, when these data were plotted against their permeability to rat jejunum in vivo, it became obvious that the permeability in Caco-2 monolayer was much lower than that in rat jejunum (Fig. 3).…”

Section: Resultsmentioning

confidence: 97%

“…7) However, from a kinetic analysis on concentration-dependent permeability, it was revealed that PepT1 expressed in Caco-2 cells possesses almost the same a‹nity to CEX with that determined in rat small intestine. 14) For other drugs such as CETB and CFIX, compatible K m value was detected in Caco-2 cells with that in the experiment using brush-border membrane vesicles prepared from rat intestinal epithelial cells. [15][16][17] Although Km values of those drugs in human small intestine have not been reported yet, it is plausible to consider that PepT1 expressed in Caco-2 cells and human intestinal cells show the similar a‹nity to its substrates since Caco-2 cells are human origin.…”

Section: Discussionmentioning

confidence: 98%

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New Methods to Evaluate Intestinal Drug Absorption Mediated by Oligopeptide Transporter from In vitro Study using Caco-2 Cells

Yamashita

Hattori

Shimada

et al. 2002

Drug Metabolism and Pharmacokinetics

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The aim of the present work is to develop a convenient and rapid screening system in vitro for intestinal drug absorption mediated by oligopeptide transporter (PepT1). In this study, (1) Transports of cephalexin (CEX) and L-phenylalanine (L-Phe) across Caco-2 monolayers were measured and compared with those of passively transported drugs, (2) Inhibitory effects of various drugs on the transport of [(14)C]glycylsarcosine (Gly-Sar) across Caco-2 monolayers were measured and correlated with their in vivo permeability to rat small intestine, (3) Intracellular pH-change induced by co-transport of drugs with proton into Caco-2 cells was monitored by using Fluorometric Imaging Plate Reader (FLIPR, Molecular Devices Corp.). Concentration-dependent transport was observed in Caco-2 monolayers for CEX and L-Phe, although their permeability was relatively low compared to those of passively transported drugs. Inhibitory effects of various drugs including beta-lactam antibiotics and angiotensin converting enzyme-inhibitors on the transport of Gly-Sar correlated well with their in vivo permeability to rat small intestine. It was demonstrated that CEX, but not cefazolin, induced gradual decrease in the intracellular pH of Caco-2 cells. The degree of intracellular pH-change caused by various drugs showed a sigmoidal or saturable relationship with their permeability to rat small intestine. These in vitro approaches with Caco-2 cells should be useful to evaluate in vivo intestinal permeability of drugs mediated by PepT1, suggesting a possibility of high throughput screening of drug absorption.

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Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 98%

New Methods to Evaluate Intestinal Drug Absorption Mediated by Oligopeptide Transporter from In vitro Study using Caco-2 Cells

Yamashita

Hattori

Shimada

et al. 2002

Drug Metabolism and Pharmacokinetics

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“…Over the past 10 years, our previous paper and various others [1][2][3][4][5][6][7][8][9] have clearly demonstrated that some drugs can be transported in the small intestine using the above mentioned carriers. This implies the existence of inhibition phenomena between drugs and nutrients.…”

Section: Introductionmentioning

confidence: 95%

Interaction of Taurine on Baclofen Intestinal Absorption: A Nonlinear Mathematical Treatment using Differential Equations to Describe Kinetic Inhibition Models

Moll-Navarro

Merino

Casabó

et al. 1996

Journal of Pharmaceutical Sciences

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Previous studies showed that the in situ absorption of baclofen in rat jejunum was inhibited by beta-alanine, a nonessential amino acid, and therefore mediated, at least in part, by some beta-amino acid carrier. In this paper a similar study was undertaken using taurine, a sulfonic beta-amino acid, in order to evaluate its effect and to establish a general inhibition model. To achieve this goal, remaining concentrations of inhibitor were also measured and incorporated into the model. Previously, kinetic absorption in situ parameters for taurine in free solution were obtained: Vm = 27.73 +/- 9.99 mM h-1, K(m) = 8.06 +/- 2.82 mM, Ka (passive difussion component) = 0.40 +/- 0.28 h-1. Isotonic solutions containing 0.5 mM baclofen with starting taurine concentrations ranging from 0 to 100 mM were perfused in rat jejunum, and the remaining concentrations of both compounds were measured. The apparent rate pseudoconstant of the drug clearly decreased as the remaining taurine concentration increased. The interaction can be described as a complete competitive inhibition plus a second component, K, noninhibited, K = 0.58 (+/- 0.03) h-1, Ki = 20.62 (+/- 4.04) mM, Vmi = 28.12 (+/- 6.12) mM h-1, Kmi = 11.71 (+/- 2.53) mM, Kai = 0.47 (+/- 0.10) h-1. A residual absorption of baclofen in the presence of high taurine concentrations was observed, which should be attributed to another transport system not associated with the taurine carrier. In order to elucidate whether or not taurine and beta-alanine carriers are two separate entities that baclofen can use for absorption, further experiments using beta-alanine and taurine together as inhibitors (baclofen, 0.5 mM; beta-alanine, 50 mM, and taurine, 50 mM) were developed. Results indicated that baclofen and both amino acids share the same carrier in the intestinal absorption process. We have completed studies using leucine, taurine, and GABA together as inhibitors of drug absorption. An isotonic perfusion solution of 0.5 mM baclofen in the presence of 50 mM leucine, 25 mM taurine, and 25 mM GABA was perfused. Under these conditions the absorption rate pseudoconstant of baclofen decreases until 0.080 h-1 (+/- 0.069). Practical implications of these phenomena are briefly discussed.

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“…Equation 2 was used to describe the permeation of formycin B and thymidine in the presence of a putative competitive inhibitor (d4T), 33 where I and K′i are the concentration and the affinity constant of d4T, respectively. Equations 1 and 2 were fitted simultaneously to the experimentally determined permeability of thymidine and formycin B in the presence and absence of d4T in both rat and rabbit BBMV.…”

Section: Introductionmentioning

confidence: 99%

Oral Absorption of Anti-Acquired Immune Deficiency Syndrome Nucleoside Analogues. 2. Carrier-Mediated Intestinal Transport of Stavudine in Rat and Rabbit Preparations†

Waclawski

Sinko

1996

Journal of Pharmaceutical Sciences

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The intestinal transport and metabolism of stavudine (d4T), a nucleoside analogue of thymidine used in the treatment of AIDS, was studied using single-pass intestinal perfusion (SPIP), intestinal brush-border membrane vesicles (BBMV), and mucosal homogenates in rats and rabbits. In the SPIP, d4T demonstrated concentration-dependent mean wall permeability (P+/-w) at perfusate concentrations ranging from 0.001 to 25 mM. In coperfusion studies using 0.1 mM thymidine, 1 mM formycin B, or 5 microM NBTI as putative inhibitors of d4T transport, the P+/-w of 5 microM d4T was reduced to 48%, 62%, and 70% of the control value, respectively, suggesting the involvement of multiple nucleoside carriers in the intestinal uptake of d4T. d4T uptake in rat BBMV was significantly greater in the presence of a sodium ion gradient compared with a sodium-free (choline) gradient. The permeability of d4T, in the presence of a sodium gradient, was concentration-dependent and inhibited by 10 mM thymidine but not significantly reduced by 10 mM formycin B. In the presence of 10 microM NBTI, the permeability of d4T was not inhibited; however; the binding of d4T to rat and rabbit BBMV was significantly reduced. Formycin B did not significantly reduce the d4T uptake in rat or rabbit BBMV suggesting that d4T does not interact with the purine-selective N1 nucleoside carrier. However, because formycin B inhibited d4T uptake in the SPIP and since d4T inhibited formycin B uptake in rat but not rabbit BBMV, it appears to interact with the N3 carrier which has been demonstrated in rat but not rabbit intestine. Also, an interaction with the sodium-independent facilitative transporter at the basolateral membrane cannot be ruled out. The low hybrid K(m) and high passive permeability of d4T likely account for the lack of saturable absorption behavior observed in humans, whereas the brush-border and intracellular stability of d4T preserve the high bioavailability observed after oral dosing.

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Characterization of the Oral Absorption of β-Lactam Antibiotics II: Competitive Absorption and Peptide Carrier Specificity

Cited by 50 publications

References 13 publications

New Methods to Evaluate Intestinal Drug Absorption Mediated by Oligopeptide Transporter from In vitro Study using Caco-2 Cells

New Methods to Evaluate Intestinal Drug Absorption Mediated by Oligopeptide Transporter from In vitro Study using Caco-2 Cells

Interaction of Taurine on Baclofen Intestinal Absorption: A Nonlinear Mathematical Treatment using Differential Equations to Describe Kinetic Inhibition Models

Oral Absorption of Anti-Acquired Immune Deficiency Syndrome Nucleoside Analogues. 2. Carrier-Mediated Intestinal Transport of Stavudine in Rat and Rabbit Preparations†

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