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Hazel H Szeto - One of the best experts on this subject based on the ideXlab platform.

  • transcellular transport of a highly polar 3 net charge opioid tetrapeptide
    2003
    Co-Authors: Kesheng Zhao, Guomin Zhao, Peter W. Schiller, Hazel H Szeto
    Abstract:

    Oligopeptides are generally thought to have Poor Permeability across biological membranes. Recent studies, however, suggest significant distribution of [Dmt 1 ]DALDA (Dmt-d-Arg-Phe-Lys-NH 2 ; Dmt is 2′,6′-dimethyltyrosine), a 3+ net charge opioid peptide, to the brain and spinal cord after subcutaneous administration. Peptide transporters (PEPT1 and PEPT2) play a major role in the uptake of di- and tripeptides across cell membranes, but their ability to transport tetrapeptides is not clear. The purpose of this study was to determine whether [Dmt 1 ]DALDA can translocate across Caco-2 cell monolayers and whether PEPT1 plays a role in the uptake process. Our results show that [ 3 H][Dmt 1 ]DALDA can readily translocate across Caco-2 cells, with a Permeability coefficient estimated to be 1.24 × 10 −5 cm/s. When incubated with Caco-2 cells, [ 3 H][Dmt 1 ]DALDA was detected in cell lysates by 5 min. The internalization of [Dmt 1 ]DALDA was confirmed visually with a fluorescent [Dmt 1 ]DALDA analog (H-Dmt-d-Arg-Phe-dnsDap-NH 2 ; dnsDap is β-dansyl-l-α,β-diaminopropionic acid). The uptake of [ 3 H][Dmt 1 ]DALDA was concentration-dependent but temperature- and pH-independent. Treatment with diethylpyrocarbonate (DEPC) inhibited [ 14 C]glycine-sarcosine uptake but increased [ 3 H][Dmt 1 ]DALDA uptake 34-fold. These findings suggest that PEPT1 is not involved in [Dmt 1 ]DALDA internalization. [Dmt 1 ]DALDA uptake was also observed in SH-SY5Y, human embryonic kidney 293, and CRFK cells, and was independent of whether the cells expressed opioid receptors. The efflux of [ 3 H][Dmt 1 ]DALDA from Caco-2 cells was temperature-dependent and was inhibited by DEPC, but was not affected by verapamil, an inhibitor of P-glycoprotein. These data show transcellular translocation of a highly polar 3+ charge tetrapeptide and suggest that [Dmt 1 ]DALDA may not only distribute across the blood-brain barrier but also it may even have reasonable oral absorption.

  • transcellular transport of a highly polar 3 net charge opioid tetrapeptide
    2003
    Co-Authors: Kesheng Zhao, Guomin Zhao, Peter W. Schiller, Guoxiong Luo, Hazel H Szeto
    Abstract:

    Oligopeptides are generally thought to have Poor Permeability across biological membranes. Recent studies, however, suggest significant distribution of [Dmt1]DALDA (Dmt-D-Arg-Phe-Lys-NH2; Dmt is 2',6'-dimethyltyrosine), a 3+ net charge opioid peptide, to the brain and spinal cord after subcutaneous administration. Peptide transporters (PEPT1 and PEPT2) play a major role in the uptake of di- and tripeptides across cell membranes, but their ability to transport tetrapeptides is not clear. The purpose of this study was to determine whether [Dmt1]DALDA can translocate across Caco-2 cell monolayers and whether PEPT1 plays a role in the uptake process. Our results show that [3H][Dmt1]DALDA can readily translocate across Caco-2 cells, with a Permeability coefficient estimated to be 1.24 x 10(-5) cm/s. When incubated with Caco-2 cells, [3H][Dmt1]DALDA was detected in cell lysates by 5 min. The internalization of [Dmt1]DALDA was confirmed visually with a fluorescent [Dmt1]DALDA analog (H-Dmt-D-Arg-Phe-dnsDap-NH2; dnsDap is beta-dansyl-L-alpha,beta-diaminopropionic acid). The uptake of [3H][Dmt1]DALDA was concentration-dependent but temperature- and pH-independent. Treatment with diethylpyrocarbonate (DEPC) inhibited [14C]glycine-sarcosine uptake but increased [3H][Dmt1]DALDA uptake 34-fold. These findings suggest that PEPT1 is not involved in [Dmt1]DALDA internalization. [Dmt1]DALDA uptake was also observed in SH-SY5Y, human embryonic kidney 293, and CRFK cells, and was independent of whether the cells expressed opioid receptors. The efflux of [3H][Dmt1]DALDA from Caco-2 cells was temperature-dependent and was inhibited by DEPC, but was not affected by verapamil, an inhibitor of P-glycoprotein. These data show transcellular translocation of a highly polar 3+ charge tetrapeptide and suggest that [Dmt1]DALDA may not only distribute across the blood-brain barrier but also it may even have reasonable oral absorption.

Kesheng Zhao - One of the best experts on this subject based on the ideXlab platform.

  • transcellular transport of a highly polar 3 net charge opioid tetrapeptide
    2003
    Co-Authors: Kesheng Zhao, Guomin Zhao, Peter W. Schiller, Hazel H Szeto
    Abstract:

    Oligopeptides are generally thought to have Poor Permeability across biological membranes. Recent studies, however, suggest significant distribution of [Dmt 1 ]DALDA (Dmt-d-Arg-Phe-Lys-NH 2 ; Dmt is 2′,6′-dimethyltyrosine), a 3+ net charge opioid peptide, to the brain and spinal cord after subcutaneous administration. Peptide transporters (PEPT1 and PEPT2) play a major role in the uptake of di- and tripeptides across cell membranes, but their ability to transport tetrapeptides is not clear. The purpose of this study was to determine whether [Dmt 1 ]DALDA can translocate across Caco-2 cell monolayers and whether PEPT1 plays a role in the uptake process. Our results show that [ 3 H][Dmt 1 ]DALDA can readily translocate across Caco-2 cells, with a Permeability coefficient estimated to be 1.24 × 10 −5 cm/s. When incubated with Caco-2 cells, [ 3 H][Dmt 1 ]DALDA was detected in cell lysates by 5 min. The internalization of [Dmt 1 ]DALDA was confirmed visually with a fluorescent [Dmt 1 ]DALDA analog (H-Dmt-d-Arg-Phe-dnsDap-NH 2 ; dnsDap is β-dansyl-l-α,β-diaminopropionic acid). The uptake of [ 3 H][Dmt 1 ]DALDA was concentration-dependent but temperature- and pH-independent. Treatment with diethylpyrocarbonate (DEPC) inhibited [ 14 C]glycine-sarcosine uptake but increased [ 3 H][Dmt 1 ]DALDA uptake 34-fold. These findings suggest that PEPT1 is not involved in [Dmt 1 ]DALDA internalization. [Dmt 1 ]DALDA uptake was also observed in SH-SY5Y, human embryonic kidney 293, and CRFK cells, and was independent of whether the cells expressed opioid receptors. The efflux of [ 3 H][Dmt 1 ]DALDA from Caco-2 cells was temperature-dependent and was inhibited by DEPC, but was not affected by verapamil, an inhibitor of P-glycoprotein. These data show transcellular translocation of a highly polar 3+ charge tetrapeptide and suggest that [Dmt 1 ]DALDA may not only distribute across the blood-brain barrier but also it may even have reasonable oral absorption.

  • transcellular transport of a highly polar 3 net charge opioid tetrapeptide
    2003
    Co-Authors: Kesheng Zhao, Guomin Zhao, Peter W. Schiller, Guoxiong Luo, Hazel H Szeto
    Abstract:

    Oligopeptides are generally thought to have Poor Permeability across biological membranes. Recent studies, however, suggest significant distribution of [Dmt1]DALDA (Dmt-D-Arg-Phe-Lys-NH2; Dmt is 2',6'-dimethyltyrosine), a 3+ net charge opioid peptide, to the brain and spinal cord after subcutaneous administration. Peptide transporters (PEPT1 and PEPT2) play a major role in the uptake of di- and tripeptides across cell membranes, but their ability to transport tetrapeptides is not clear. The purpose of this study was to determine whether [Dmt1]DALDA can translocate across Caco-2 cell monolayers and whether PEPT1 plays a role in the uptake process. Our results show that [3H][Dmt1]DALDA can readily translocate across Caco-2 cells, with a Permeability coefficient estimated to be 1.24 x 10(-5) cm/s. When incubated with Caco-2 cells, [3H][Dmt1]DALDA was detected in cell lysates by 5 min. The internalization of [Dmt1]DALDA was confirmed visually with a fluorescent [Dmt1]DALDA analog (H-Dmt-D-Arg-Phe-dnsDap-NH2; dnsDap is beta-dansyl-L-alpha,beta-diaminopropionic acid). The uptake of [3H][Dmt1]DALDA was concentration-dependent but temperature- and pH-independent. Treatment with diethylpyrocarbonate (DEPC) inhibited [14C]glycine-sarcosine uptake but increased [3H][Dmt1]DALDA uptake 34-fold. These findings suggest that PEPT1 is not involved in [Dmt1]DALDA internalization. [Dmt1]DALDA uptake was also observed in SH-SY5Y, human embryonic kidney 293, and CRFK cells, and was independent of whether the cells expressed opioid receptors. The efflux of [3H][Dmt1]DALDA from Caco-2 cells was temperature-dependent and was inhibited by DEPC, but was not affected by verapamil, an inhibitor of P-glycoprotein. These data show transcellular translocation of a highly polar 3+ charge tetrapeptide and suggest that [Dmt1]DALDA may not only distribute across the blood-brain barrier but also it may even have reasonable oral absorption.

Peter W. Schiller - One of the best experts on this subject based on the ideXlab platform.

  • transcellular transport of a highly polar 3 net charge opioid tetrapeptide
    2003
    Co-Authors: Kesheng Zhao, Guomin Zhao, Peter W. Schiller, Hazel H Szeto
    Abstract:

    Oligopeptides are generally thought to have Poor Permeability across biological membranes. Recent studies, however, suggest significant distribution of [Dmt 1 ]DALDA (Dmt-d-Arg-Phe-Lys-NH 2 ; Dmt is 2′,6′-dimethyltyrosine), a 3+ net charge opioid peptide, to the brain and spinal cord after subcutaneous administration. Peptide transporters (PEPT1 and PEPT2) play a major role in the uptake of di- and tripeptides across cell membranes, but their ability to transport tetrapeptides is not clear. The purpose of this study was to determine whether [Dmt 1 ]DALDA can translocate across Caco-2 cell monolayers and whether PEPT1 plays a role in the uptake process. Our results show that [ 3 H][Dmt 1 ]DALDA can readily translocate across Caco-2 cells, with a Permeability coefficient estimated to be 1.24 × 10 −5 cm/s. When incubated with Caco-2 cells, [ 3 H][Dmt 1 ]DALDA was detected in cell lysates by 5 min. The internalization of [Dmt 1 ]DALDA was confirmed visually with a fluorescent [Dmt 1 ]DALDA analog (H-Dmt-d-Arg-Phe-dnsDap-NH 2 ; dnsDap is β-dansyl-l-α,β-diaminopropionic acid). The uptake of [ 3 H][Dmt 1 ]DALDA was concentration-dependent but temperature- and pH-independent. Treatment with diethylpyrocarbonate (DEPC) inhibited [ 14 C]glycine-sarcosine uptake but increased [ 3 H][Dmt 1 ]DALDA uptake 34-fold. These findings suggest that PEPT1 is not involved in [Dmt 1 ]DALDA internalization. [Dmt 1 ]DALDA uptake was also observed in SH-SY5Y, human embryonic kidney 293, and CRFK cells, and was independent of whether the cells expressed opioid receptors. The efflux of [ 3 H][Dmt 1 ]DALDA from Caco-2 cells was temperature-dependent and was inhibited by DEPC, but was not affected by verapamil, an inhibitor of P-glycoprotein. These data show transcellular translocation of a highly polar 3+ charge tetrapeptide and suggest that [Dmt 1 ]DALDA may not only distribute across the blood-brain barrier but also it may even have reasonable oral absorption.

  • transcellular transport of a highly polar 3 net charge opioid tetrapeptide
    2003
    Co-Authors: Kesheng Zhao, Guomin Zhao, Peter W. Schiller, Guoxiong Luo, Hazel H Szeto
    Abstract:

    Oligopeptides are generally thought to have Poor Permeability across biological membranes. Recent studies, however, suggest significant distribution of [Dmt1]DALDA (Dmt-D-Arg-Phe-Lys-NH2; Dmt is 2',6'-dimethyltyrosine), a 3+ net charge opioid peptide, to the brain and spinal cord after subcutaneous administration. Peptide transporters (PEPT1 and PEPT2) play a major role in the uptake of di- and tripeptides across cell membranes, but their ability to transport tetrapeptides is not clear. The purpose of this study was to determine whether [Dmt1]DALDA can translocate across Caco-2 cell monolayers and whether PEPT1 plays a role in the uptake process. Our results show that [3H][Dmt1]DALDA can readily translocate across Caco-2 cells, with a Permeability coefficient estimated to be 1.24 x 10(-5) cm/s. When incubated with Caco-2 cells, [3H][Dmt1]DALDA was detected in cell lysates by 5 min. The internalization of [Dmt1]DALDA was confirmed visually with a fluorescent [Dmt1]DALDA analog (H-Dmt-D-Arg-Phe-dnsDap-NH2; dnsDap is beta-dansyl-L-alpha,beta-diaminopropionic acid). The uptake of [3H][Dmt1]DALDA was concentration-dependent but temperature- and pH-independent. Treatment with diethylpyrocarbonate (DEPC) inhibited [14C]glycine-sarcosine uptake but increased [3H][Dmt1]DALDA uptake 34-fold. These findings suggest that PEPT1 is not involved in [Dmt1]DALDA internalization. [Dmt1]DALDA uptake was also observed in SH-SY5Y, human embryonic kidney 293, and CRFK cells, and was independent of whether the cells expressed opioid receptors. The efflux of [3H][Dmt1]DALDA from Caco-2 cells was temperature-dependent and was inhibited by DEPC, but was not affected by verapamil, an inhibitor of P-glycoprotein. These data show transcellular translocation of a highly polar 3+ charge tetrapeptide and suggest that [Dmt1]DALDA may not only distribute across the blood-brain barrier but also it may even have reasonable oral absorption.

Guomin Zhao - One of the best experts on this subject based on the ideXlab platform.

  • transcellular transport of a highly polar 3 net charge opioid tetrapeptide
    2003
    Co-Authors: Kesheng Zhao, Guomin Zhao, Peter W. Schiller, Hazel H Szeto
    Abstract:

    Oligopeptides are generally thought to have Poor Permeability across biological membranes. Recent studies, however, suggest significant distribution of [Dmt 1 ]DALDA (Dmt-d-Arg-Phe-Lys-NH 2 ; Dmt is 2′,6′-dimethyltyrosine), a 3+ net charge opioid peptide, to the brain and spinal cord after subcutaneous administration. Peptide transporters (PEPT1 and PEPT2) play a major role in the uptake of di- and tripeptides across cell membranes, but their ability to transport tetrapeptides is not clear. The purpose of this study was to determine whether [Dmt 1 ]DALDA can translocate across Caco-2 cell monolayers and whether PEPT1 plays a role in the uptake process. Our results show that [ 3 H][Dmt 1 ]DALDA can readily translocate across Caco-2 cells, with a Permeability coefficient estimated to be 1.24 × 10 −5 cm/s. When incubated with Caco-2 cells, [ 3 H][Dmt 1 ]DALDA was detected in cell lysates by 5 min. The internalization of [Dmt 1 ]DALDA was confirmed visually with a fluorescent [Dmt 1 ]DALDA analog (H-Dmt-d-Arg-Phe-dnsDap-NH 2 ; dnsDap is β-dansyl-l-α,β-diaminopropionic acid). The uptake of [ 3 H][Dmt 1 ]DALDA was concentration-dependent but temperature- and pH-independent. Treatment with diethylpyrocarbonate (DEPC) inhibited [ 14 C]glycine-sarcosine uptake but increased [ 3 H][Dmt 1 ]DALDA uptake 34-fold. These findings suggest that PEPT1 is not involved in [Dmt 1 ]DALDA internalization. [Dmt 1 ]DALDA uptake was also observed in SH-SY5Y, human embryonic kidney 293, and CRFK cells, and was independent of whether the cells expressed opioid receptors. The efflux of [ 3 H][Dmt 1 ]DALDA from Caco-2 cells was temperature-dependent and was inhibited by DEPC, but was not affected by verapamil, an inhibitor of P-glycoprotein. These data show transcellular translocation of a highly polar 3+ charge tetrapeptide and suggest that [Dmt 1 ]DALDA may not only distribute across the blood-brain barrier but also it may even have reasonable oral absorption.

  • transcellular transport of a highly polar 3 net charge opioid tetrapeptide
    2003
    Co-Authors: Kesheng Zhao, Guomin Zhao, Peter W. Schiller, Guoxiong Luo, Hazel H Szeto
    Abstract:

    Oligopeptides are generally thought to have Poor Permeability across biological membranes. Recent studies, however, suggest significant distribution of [Dmt1]DALDA (Dmt-D-Arg-Phe-Lys-NH2; Dmt is 2',6'-dimethyltyrosine), a 3+ net charge opioid peptide, to the brain and spinal cord after subcutaneous administration. Peptide transporters (PEPT1 and PEPT2) play a major role in the uptake of di- and tripeptides across cell membranes, but their ability to transport tetrapeptides is not clear. The purpose of this study was to determine whether [Dmt1]DALDA can translocate across Caco-2 cell monolayers and whether PEPT1 plays a role in the uptake process. Our results show that [3H][Dmt1]DALDA can readily translocate across Caco-2 cells, with a Permeability coefficient estimated to be 1.24 x 10(-5) cm/s. When incubated with Caco-2 cells, [3H][Dmt1]DALDA was detected in cell lysates by 5 min. The internalization of [Dmt1]DALDA was confirmed visually with a fluorescent [Dmt1]DALDA analog (H-Dmt-D-Arg-Phe-dnsDap-NH2; dnsDap is beta-dansyl-L-alpha,beta-diaminopropionic acid). The uptake of [3H][Dmt1]DALDA was concentration-dependent but temperature- and pH-independent. Treatment with diethylpyrocarbonate (DEPC) inhibited [14C]glycine-sarcosine uptake but increased [3H][Dmt1]DALDA uptake 34-fold. These findings suggest that PEPT1 is not involved in [Dmt1]DALDA internalization. [Dmt1]DALDA uptake was also observed in SH-SY5Y, human embryonic kidney 293, and CRFK cells, and was independent of whether the cells expressed opioid receptors. The efflux of [3H][Dmt1]DALDA from Caco-2 cells was temperature-dependent and was inhibited by DEPC, but was not affected by verapamil, an inhibitor of P-glycoprotein. These data show transcellular translocation of a highly polar 3+ charge tetrapeptide and suggest that [Dmt1]DALDA may not only distribute across the blood-brain barrier but also it may even have reasonable oral absorption.

Guoxiong Luo - One of the best experts on this subject based on the ideXlab platform.

  • transcellular transport of a highly polar 3 net charge opioid tetrapeptide
    2003
    Co-Authors: Kesheng Zhao, Guomin Zhao, Peter W. Schiller, Guoxiong Luo, Hazel H Szeto
    Abstract:

    Oligopeptides are generally thought to have Poor Permeability across biological membranes. Recent studies, however, suggest significant distribution of [Dmt1]DALDA (Dmt-D-Arg-Phe-Lys-NH2; Dmt is 2',6'-dimethyltyrosine), a 3+ net charge opioid peptide, to the brain and spinal cord after subcutaneous administration. Peptide transporters (PEPT1 and PEPT2) play a major role in the uptake of di- and tripeptides across cell membranes, but their ability to transport tetrapeptides is not clear. The purpose of this study was to determine whether [Dmt1]DALDA can translocate across Caco-2 cell monolayers and whether PEPT1 plays a role in the uptake process. Our results show that [3H][Dmt1]DALDA can readily translocate across Caco-2 cells, with a Permeability coefficient estimated to be 1.24 x 10(-5) cm/s. When incubated with Caco-2 cells, [3H][Dmt1]DALDA was detected in cell lysates by 5 min. The internalization of [Dmt1]DALDA was confirmed visually with a fluorescent [Dmt1]DALDA analog (H-Dmt-D-Arg-Phe-dnsDap-NH2; dnsDap is beta-dansyl-L-alpha,beta-diaminopropionic acid). The uptake of [3H][Dmt1]DALDA was concentration-dependent but temperature- and pH-independent. Treatment with diethylpyrocarbonate (DEPC) inhibited [14C]glycine-sarcosine uptake but increased [3H][Dmt1]DALDA uptake 34-fold. These findings suggest that PEPT1 is not involved in [Dmt1]DALDA internalization. [Dmt1]DALDA uptake was also observed in SH-SY5Y, human embryonic kidney 293, and CRFK cells, and was independent of whether the cells expressed opioid receptors. The efflux of [3H][Dmt1]DALDA from Caco-2 cells was temperature-dependent and was inhibited by DEPC, but was not affected by verapamil, an inhibitor of P-glycoprotein. These data show transcellular translocation of a highly polar 3+ charge tetrapeptide and suggest that [Dmt1]DALDA may not only distribute across the blood-brain barrier but also it may even have reasonable oral absorption.