A physical model for the simultaneous membrane transport and metabolism of drugs

Ho, Norman F.H.; Park, J. Y.; Morozowich, W.; Higuchi, William I.

doi:10.1016/0022-5193(76)90112-0

Cited by 11 publications

(3 citation statements)

References 9 publications

(1 reference statement)

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“…Ultimately, it was found that a parabolic relationship of catalyst activity with XSA gave the best description of catalyst activity (Results, Section 2.4 and Figure 4). Non-linear correlations (parabolic, 5,98 sigmoidal, 99 hyperbolic, 100 and bilinear 101 ) of the phase transfer rate of small molecules with polar surface area and lipophilicity are often observed. In this case, the catalyst activity levels off between XSA values of ~80 and 100 Å 2 (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

A Systematic Investigation of Quaternary Ammonium Ions as Asymmetric Phase-Transfer Catalysts. Application of Quantitative Structure Activity/Selectivity Relationships

2011

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While the synthetic utility of asymmetric phase transfer catalysis continues to expand, the number of proven catalyst types and design criteria remains limited. At the origin of this scarcity is a lack in understanding of how catalyst structural features affect the rate and enantioselectivity of phase transfer catalyzed reactions. Described in this paper is the development of quantitative structure-activity relationships (QSAR) and -selectivity relationships (QSSR) for the alkylation of a protected glycine imine with libraries of quaternary ammonium ion catalysts. Catalyst descriptors including ammonium ion accessibility, interfacial adsorption affinity, and partition coefficient were found to correlate meaningfully with catalyst activity. The physical nature of the descriptors was rationalized through differing contributions of the interfacial and extraction mechanisms to the reaction under study. The variation in the observed enantioselectivity was rationalized employing a comparative molecular field analysis (CoMFA) using both the steric and electrostatic fields of the catalysts. A qualitative analysis of the developed model reveals preferred regions for catalyst binding to afford both configurations of the alkylated product.

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Section: Discussionmentioning

confidence: 99%

A Systematic Investigation of Quaternary Ammonium Ions as Asymmetric Phase-Transfer Catalysts. Application of Quantitative Structure Activity/Selectivity Relationships

2011

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“…As a first approximation, we assumed that solute influx through this interface followed Fick’s law and was proportional to the concentration gradient and a transport rate constant k . As widely used in membrane transport problems [29-31], the first principle (mass conservation) can be applied to the half space consisting of the periosteum and underlying bone (Eq. 1), i.e., the influx of tracer from the bath through the interface z = 0 (the left side) equaled the tracer accumulation within the region of interest during each time step (the right side):

k (t) \int_{t_{(n - 1)}}^{t_{(n)}} \frac{\partial C}{\partial z} d t = \int_{z = 0}^{z = \infty} C_{(t = t_{(n)})} d z - \int_{z = 0}^{z = \infty} C_{(t = t_{(n - 1)})} d z

From Eq.…”

Section: Methodsmentioning

confidence: 99%

Imaging and quantifying solute transport across periosteum: Implications for muscle–bone crosstalk

Lai

Price

Lü

et al. 2014

Bone

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Muscle and bone are known to act as a functional unit and communicate biochemically during tissue development and maintenance. Muscle-derived factors (myokines) have been found to affect bone functions in vitro. However, the transport times of myokines to penetrate into bone, a critical step required for local muscle-bone crosstalk, have not been quantified in situ or in vivo. In this study, we investigated the permeability of the periosteum, a major barrier to muscle-bone crosstalk by tracking and modeling fluorescent tracers that mimic myokines under confocal microscopy. Periosteal surface boundaries and tracer penetration within the boundaries were imaged in intact murine tibiae using reflected light and time-series xz confocal imaging, respectively. Four fluorescent tracers including sodium fluorescein (376Da) and dextrans (3kDa, 10kDa and 40kDa) were chosen because they represented a wide range of molecular weights (MW) of myokines. We found that i) murine periosteum was permeable to the three smaller tracers while the 40kDa could not penetrate beyond 40% of the outer periosteum within 8 hours, suggesting that periosteum is semi-permeable with a cut-off MW of approximately 40kDa, and ii) the characteristic penetration time through the periosteum (~60μm thick) increased with tracer MW and fit well with a relationship (((tc[sec]=−(4.43×104)−0.57×(MW[Da]−4×104)−8.65×108MW[Da]−4×104)), from which, the characteristic penetration times of various myokines were extrapolated. To achieve effective muscle-bone crosstalk, likely signaling candidates should have shorter penetration time than their bioactive time, which we assumed to be 5 times of the molecule’s half-life time in the body. Myokines such as PGE2, IGF-1, IL-15 and FGF-2 were predicted to satisfy this requirement. In summary, a novel imaging approach was developed and used to investigate the transport of myokine mimicking-tracers through the periosteum, enabling further quantitative studies of muscle-bone communication in physiologically normal and pathological conditions.

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“…Mechanisms of membrane diffusion have been described in the pharmaceutical literature to elucidate the physical, anatomical, and physiological factors that influence molecular transport processes across bio-membranes [236][237][238][239][240][241] . Initial biophysical models examining flux and metabolism were based on Fickian diffusion coupled with first-order degradation kinetics of drug substrates [242][243][244] . Although it can be argued that first-order enzymatic reaction kinetics accurately describes degradation rates for low substrate concentrations, a more complex treatment of metabolism was necessary for the higher substrate concentrations used in drug formulations permeating across a viable membrane exhibiting saturable enzymatic activity.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450-mediated drug metabolizing activity in the nasal mucosa

Dhamankar¹

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Pre-systemic elimination by local enzymatic degradation can play a key role in limiting the bioavailability of intranasally administered drugs. Despite remarkable advancement in the characterization of the nasal biotransformative enzymes, knowledge of the role of the nasal mucosa in limiting bioavailability of therapeutic agents is still inadequate. The aim of this work was to evaluate the expression and substrate biotransformation activity of cytochrome P450 enzymes in the nasal mucosa using bovine olfactory and respiratory explants as in vitro models. Gene expression and localization of major CYP450 isoforms in the nasal mucosa were examined using RT-PCR and immunohistochemistry. The bovine nasal mucosa showed abundant expression of CYP2A6 and 3A4 genes whereas 1A1, 1A2, 2C9, and 2C19 isoforms were expressed at much lower levels. The CYP450 proteins were observed to be present in the epithelial layer and in submucosal glandular cells. The diffusion of melatonin, a CYP1A2 substrate, and the appearance of 6-hydroxymelatonin, its primary metabolite, across bovine olfactory and respiratory explants was measured, and nasal olfactory and respiratory microsomal preparations were used to quantify the kinetic parameters for melatonin 6-hydroxylation. Results indicated that bovine olfactory and respiratory CYP450 isoforms were metabolically active towards melatonin metabolism, and the respiratory mucosa demonstrated the greatest melatonin 6-hydroxylation activity. Numerical simulations were used to probe the effects of the relative magnitudes of the permeability coefficient and enzymatic parameters on net substrate mass transfer across nasal mucosal tissues. The simulations indicated that the concentration gradient of This work could not have been completed without the love and support from my family and friends. I would like to thank my mom, dad, and brother for their unconditional love and encouragement. Also, sincere thanks to Bhakti and all my friends in Iowa City for making the graduate study an awesome experience. Finally, I would like to thank Girish for making this journey a memorable one! v ABSTRACT Pre-systemic elimination by local enzymatic degradation can play a key role in limiting the bioavailability of intranasally administered drugs. Despite remarkable advancement in the characterization of the nasal biotransformative enzymes, knowledge of the role of the nasal mucosa in limiting bioavailability of therapeutic agents is still inadequate. The aim of this work was to evaluate the expression and substrate biotransformation activity of cytochrome P450 enzymes in the nasal mucosa using bovine olfactory and respiratory explants as in vitro models. Gene expression and localization of major CYP450 isoforms in the nasal mucosa were examined using RT-PCR and immunohistochemistry. The bovine nasal mucosa showed abundant expression of CYP2A6 and 3A4 genes whereas 1A1, 1A2, 2C9, and 2C19 isoforms were expressed at much lower levels. The CYP450 proteins were observed to be present in the epithelial layer and in submuco...

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A physical model for the simultaneous membrane transport and metabolism of drugs

Cited by 11 publications

References 9 publications

A Systematic Investigation of Quaternary Ammonium Ions as Asymmetric Phase-Transfer Catalysts. Application of Quantitative Structure Activity/Selectivity Relationships

A Systematic Investigation of Quaternary Ammonium Ions as Asymmetric Phase-Transfer Catalysts. Application of Quantitative Structure Activity/Selectivity Relationships

Imaging and quantifying solute transport across periosteum: Implications for muscle–bone crosstalk

Cytochrome P450-mediated drug metabolizing activity in the nasal mucosa

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