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  • 1
    Electronic Resource
    Electronic Resource
    Mean molecular potentials in a model lipid bilayer: A molecular dynamics simulation (1995)
    College Park, Md. : American Institute of Physics (AIP)
    The Journal of Chemical Physics 103 (1995), S. 8666-8678 
    Details
    ISSN: 1089-7690
    Source: AIP Digital Archive
    Topics: Physics , Chemistry and Pharmacology
    Notes: Various mean-field potentials in a model lipid bilayer are calculated by means of molecular dynamics (MD) simulation. The bilayer assembly consists of 200 chain molecules. The anisotropic united atom model is employed for nonbonded interactions and is extended to allow bond length to vary with time. The interfacial translational order is systematically varied and found to correlate strongly with the chain orientational order. A new torsional potential is developed and shown to give order parameters in better agreement with experiment than the Padilla–Toxvaerd potential. Nonbonded interaction reduces the trans–gauche and gauche–gauche transition barriers by 0.9—1.5 kcal/mole. The mean trans–gauche energy difference near the chain tail is close to that in liquid hydrocarbons but 0.34 kcal/mol lower than that in the highly ordered chain region. In contrast to the Marcelja model, both mean intermolecular dispersive and repulsive energies depend exponentially on the chain orientational parameter and the repulsive component has a poor and inverse correlation with the reciprocal of the chain end-to-end displacement along the bilayer normal. Inclusion of spatial heterogeneity effects of the interaction energy, a treatment similar to the Gruen model [Biochim. Biophys Acta 367, 165 (1980)], does not give a better description of the mean intermolecular interaction. A new and unified model for the mean intermolecular interaction energy is developed based on our present MD simulation data. Various possible chain configurations which are responsible for these results are discussed. Finally, our MD results suggest that, consistent with the "wobble in a cone'' model, a chain molecule can rotate freely within an angular range without being subjected to a strong potential force. © 1995 American Institute of Physics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1063/1.470124
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  • 2
    Electronic Resource
    Electronic Resource
    Molecular dissolution processes in lipid bilayers: A molecular dynamics simulation (1999)
    College Park, Md. : American Institute of Physics (AIP)
    The Journal of Chemical Physics 110 (1999), S. 1807-1818 
    Details
    ISSN: 1089-7690
    Source: AIP Digital Archive
    Topics: Physics , Chemistry and Pharmacology
    Notes: A thorough understanding of the effects of chain ordering on solute partitioning and transport across biomembranes requires a detailed account of various dissolution processes in lipid bilayers. In this study, the dissolution properties and related molecular processes for noble gases in the alkyl chain region of lipid bilayers were obtained by means of molecular dynamics simulation. The excess chemical potential exhibits a plateau value in the ordered peripheral region followed by a steep decline near the center of the bilayer. The strong entropic effects as manifested by the larger Barclay–Butler constants than commonly encountered in hydrocarbon solvents indicate that solute partitioning into membranes is driven primarily by changes of lipid chain conformation or/and an extra confinement of solute in the bilayer interior. Solute partitioning into lipid bilayers is analyzed in terms of two contributions: (1) the free energy for cavity creation to accommodate a solute, which is analyzed by scaled particle theory; and (2) the interaction energy between the inserted solute and surrounding molecules in the bilayer. The unfavorable free energy for cavity creation is found to be primarily responsible for the substantial decrease of solubility into the membranes from that into a hydrocarbon solvent (dodecane) when the solute size is increased. The observed linear decrease of the excess chemical potential with solute surface area arises from linear but opposite dependencies of the reversible work for cavity creation and the intermolecular interaction energy on solute surface area and may be described by an anisotropic surface-tension model. © 1999 American Institute of Physics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1063/1.477878
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  • 3
    Electronic Resource
    Electronic Resource
    Intrinsic Solubility Estimation and pH-Solubility Behavior of Cosalane (NSC 658586), an Extremely Hydrophobic Diprotic Acid (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1453-1459 
    Details
    ISSN: 1573-904X
    Keywords: cosalane ; solubility ; facilitated dissolution ; partition coefficient ; group contribution approach ; pH-solubility behavior
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The selection of cosalane (NSC 658586) by the National Cancer Institute for further development as a potential drug candidate for the treatment of AIDS led to the exploration of the solubility behavior of this extremely hydrophobic drug, which has an intrinsic solubility (S0) approaching 1 ng/ml. This study describes attempts to reliably measure the intrinsic solubility of cosalane and examine its pH-solubility behavior. Methods. S0 was estimated by 5 different strategies: (a) direct determination in an aqueous suspension; (b) facilitated dissolution; (c) estimation from the octanol/water partition coefficient and octanol solubility; (d) application of an empirical equation based on melting point and partition coefficient; and (e) estimation from the hydrocarbon solubility and functional group contributions for transfer from hydrocarbon to water. Results. S0 estimates using these five methods varied over a 5 × 109-fold range. Method (a) yielded the highest values, two-orders of magnitude greater than those obtained by method (b) (facilitated dissolution, 1.4 ± 0.5 ng/ml). Method (c) gave a value 20-fold higher while that from method (d) was in fair agreement with that from facilitated dissolution. Method (e) yielded a value several orders-of-magnitude lower than other methods. A molecular dynamics simulation suggests that folded conformations not accounted for by group contributions may reduce cosalane's effective hydrophobicity. Ionic equilibria calculations for this weak diprotic acid suggested a 100-fold increase in solubility per pH unit increase. The pH-solubility profile of cosalane at 25°C agreed closely with theory. Conclusions. These studies highlight the difficulty in determining solubility of very poorly soluble compounds and the possible advantage of the facilitated dissolution method. The diprotic nature of cosalane enabled a solubility enhancement of 〉107-fold by simple pH adjustment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016059008464
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  • 4
    Electronic Resource
    Electronic Resource
    Enhanced Oral Bioavailability of DDI After Administration of 6-Cl-ddP, an Adenosine Deaminase-Activated Prodrug, to Chronically Catheterized Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1126-1133 
    Details
    ISSN: 1573-904X
    Keywords: oral ; portal ; bioavailability ; adenosine deaminase ; prodrugs ; dideoxyinosine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. 6-Cl-2′,3′-dideoxypurine (6-Cl-ddP), an adenosine deaminase (ADA) activated prodrug of ddI, may be an effective antiretroviral agent for the treatment of AIDS dementia due to its ability to deliver increased concentrations of ddI to brain tissue. To examine the feasibility of administering this drug orally, the oral and hepatic portal bioavailabilities of 6-Cl-ddP were determined. In addition, the oral and portal bioavailabilities of ddI after administration of the prodrug were compared to those from administration of ddI itself. Methods. Pharmacokinetic and bioavailability studies were conducted in fully conscious, chronically catheterized rats in a randomized crossover design. Plasma ddI and 6-Cl-ddP concentration-time profiles were determined by HPLC. Results. 6-Cl-ddP has poor apparent oral bioavailability (7% ± 3%, n = 3) but high bioavailability after portal administration (97% ± 11%), suggesting either poor absorption or extensive gut wall metabolism. The appearance of 〉50% of the dose as ddI in the systemic circulation after an oral dose of 6-Cl-ddP rules out poor absorption of the prodrug, and confirms expectations of high ADA activity in the gastrointestinal tract. Gastric administration of 6-Cl-ddP resulted in a 〉 10-fold increase in the oral bioavailability of ddI, from 3–7% to 〉50%, and a significant decrease in the variability in apparent bioavailability. Conclusions. These data indicate that lipophilic adenosine deaminase activated prodrugs of dideoxypurine nucleosides may have limited utility for improving CNS delivery after oral administration but may be useful in enhancing the oral bioavailability of highly polar and therefore poorly absorbed dideoxynucleosides.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016299507382
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  • 5
    Electronic Resource
    Electronic Resource
    Effects of Insulin Concentration and Self-Association on the Partitioning of Its A-21 Cyclic Anhydride Intermediate to Desamido Insulin and Covalent Dimer (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1077-1084 
    Details
    ISSN: 1573-904X
    Keywords: protein stability ; insulin ; insulin dimers ; covalent aggregation ; deamidation ; chemical kinetics ; intramolecular nucleophilic catalysis ; self-association
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. In the pH range 2–5, human insulin degrades via deamidation at the A-21 asn and covalent dimerization. Both products form via a common cyclic anhydride intermediate, a product of intramolecular nucleophilic attack by the A-21 carboxyl terminus. This study examines the influence of [insulin] and self-association on the partitioning of the intermediate to products. Methods. Insulin self-association was characterized (pH 2–4) by concentration difference spectroscopy. Deamidation rates (pH 2–4) and concurrent rates of covalent dimer formation (pH 4) were determined versus [insulin] at 35°C by initial rates. A mathematical model was developed to account for the overall rate and product composition profile versus pH and [insulin]. Results. Between pH 2–4, insulin self-associates to form non-covalent dimers with a pH independent association constant of 1.8 × 104 M −1. The overall rate of degradation is governed by intermediate formation, while product distribution is determined by competition between water and the phe B-l amino group of insulin for the anhydride. In dilute solutions, deamidation is first-order in [insulin] while covalent dimerization is second-order. Thus, deamidation predominates in dilute solutions but the fraction of covalent dimer formed increases with [insulin]. At high [insulin], self-association inhibits covalent dimer formation, preventing exclusive degradation via this pathway. The model accurately predicts a maximum in covalent dimer formation near pH 4. Conclusions. A mechanism is described which accounts for the complex dependence of insulin's degradation rate and product distribution profile on pH (between 2–5) and [insulin]. If these results can be generalized, they suggest that covalent aggregation in proteins may be inhibited by self-association.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016231019677
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  • 6
    Electronic Resource
    Electronic Resource
    Solid-State Stability of Human Insulin I. Mechanism and the Effect of Water on the Kinetics of Degradation in Lyophiles from pH 2–5 Solutions (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1142-1153 
    Details
    ISSN: 1573-904X
    Keywords: protein stability ; solid-state degradation ; deamidation ; covalent dimerization ; acyl transfer ; intramolecular catalysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Previous studies have established that in aqueous solution at low pH human insulin decomposition proceeds through a cyclic anhydride intermediate leading to the formation of both deamidated and covalent dimer products. This study examines the mechanism and kinetics of insulin degradation in the amorphous solid state (lyophilized powders) as a function of water content over a similar pH range. Methods. Solutions of 1.0 mg/mL insulin were adjusted to pH 2–5 using HC1, freeze-dried, then exposed to various relative humidities at 35°C. The water content within the powders was determined by Karl Fischer titration, and the concentrations of insulin and its degradation products were determined by HPLC. Degradation kinetics were determined by both the initial rates of product formation and insulin disappearance. Results. Semi-logarithmic plots of insulin remaining in lyophilized powders versus time were non-linear, asymptotically approaching non-zero apparent plateau values, mathematically describable by a reversible, first-order kinetic model. The rate of degradation of insulin in the solid state was observed to increase with decreasing apparent pH (‘pH’) yielding, at any given water content, solid-state ‘pH’-rate profiles parallel to the solution pH-rate profile. This ‘pH’ dependence could be accounted for in terms of the fraction of the insulin A21 carboxyl in its neutral form, with an apparent pKa of ≈4, independent of water content. Aniline trapping studies established that the mechanism of degradation of human insulin in lyophilized powders between pH 3–5 and at 35°C involves rate-limiting intramolecular nucleophilic attack of the AsnA21 C-terminal carboxylic acid onto the side-chain amide carbonyl to form a reactive cyclic anhydride intermediate, which further reacts with either water or an N-terminal primary amino group (e.g., PheB1, and GlyAl) of another insulin molecule to generate either deamidated insulin (AspA21) or an amide-linked covalent dimer (e.g., [AspA21-PheB1] or [AspA21-GlyA1]), respectively. The rate of insulin degradation in lyophilized powders at 35°C increases with water content at levels of hydration well below the suspected glass transition and approaches the rate in solution at or near the water content (20–50%) required to induce a glass transition. Conclusions. The decomposition of human insulin in lyophilized powders between pH 3–5 is a water induced solid-state reaction accelerated by the plasticization effect of sorbed water. The formation of the cyclic anhydride intermediate at A21 occurs readily even in the glassy state, presumably due to the conformational flexibility of the A21 segment even under conditions in which the insulin molecules as a whole are largely immobile.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016043715791
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  • 7
    Electronic Resource
    Electronic Resource
    Localization of Purine Metabolizing Enzymes in Bovine Brain Microvessel Endothelial Cells: An Enzymatic Blood-Brain Barrier for Dideoxynucleosides? (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1881-1886 
    Details
    ISSN: 1573-904X
    Keywords: 2′,3′-dideoxynucleoside ; bovine brain endothelial cell ; adenosine deaminase ; cytidine deaminase ; purine nucleoside phosphorylase ; enzymatic blood-brain barrier
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The specific activities of the purine and pyrimidine metabolizing enzymes, purine nucleoside phosphorylase (PNP), adenosine deaminase (ADA) and cytidine deaminase (CDA) were determined in bovine brain microvessel endothelial cells (BBMECs), whole cerebral tissue and erythrocytes. In addition, the substrate specificities (Km and Vmax) of purified calf spleen PNP for inosine and 2′,3′-dideoxyinosine (ddl) and of purified calf intestinal ADA for 2′,3′-dideoxyadenosine (ddA), 6-chloro-2′,3′-dideoxypurine (6-Cl-ddP), and 2′-β-fluoro-2′,3′-dideoxyadenosine (F-ddA) have been explored. Methods. BBMECs were isolated from bovine cerebral cortex by a two step enzymatic dispersion treatment followed by centrifugation over 50% Percoll density gradients. Activities of alkaline phosphatase, γ-glutamyl transpeptidase, ADA, PNP and CDA were determined in various tissue homogenates (cerebral cortex, BBMECs and erythrocytes). Enzyme kinetic studies were also conducted using commercially available enzymes and several nucleoside analogs of interest. Results. The activities of ADA and PNP were 42-fold and 247-fold higher in the cerebral microvessels than in the cerebral cortex, respectively, while there was no detectable CDA activity in the microvessel fraction and very little overall activity in the cortex. Conclusions. ADA and PNP may serve as an enzymatic blood-brain barrier for some of the anti-HIV dideoxynucleosides. Simulations of brain availability for ddl, ddA, 6-Cl-ddP, and F-ddA demonstrated that the quantitative significance of enzyme localization may vary dramatically, however, depending on the membrane permeability of the drug and its bioconversion rate constant within the endothelial cell.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016001712524
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  • 8
    Electronic Resource
    Electronic Resource
    Role of Brain Tissue Localized Purine Metabolizing Enzymes in the Central Nervous System Delivery of Anti-HIV Agents 2′-β-Fluoro-2,3′-Dideoxyinosine and 2′-β-Fluoro-2′,3′-Dideoxyadenosine in Rats (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 786-792 
    Details
    ISSN: 1573-904X
    Keywords: dideoxyadenosine ; blood-brain barrier ; adenosine deaminase ; purine nucleoside phosphorylase ; inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study examines the central nervous system (CNS) delivery of 2′-β-fluoro-2′,3′-dideoxyadenosine (F-ddA) and 2′-β-fluoro-2′,3′-dideoxyinosine (F-ddl), acid stable analogues of dideoxyadenosine (ddA) and dideoxyinosine (ddI) having reduced susceptibility to purine salvage pathway enzymes important in the metabolism of ddA and ddI, adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP), respectively. Their CNS delivery compared to that for ddI provides insight into the role of brain tissue ADA and PNP in these processes. Methods. Brain and cerebrospinal fluid (CSF) concentration-time profiles were obtained for F-ddI during and after intravenous infusions of F-ddl, and for both F-ddA and F-ddI after F-ddA infusions in normal rats or rats pre-treated with the ADA inhibitor 2′-deoxycoformycin (DCF). Rate constants for CNS entry, efflux and metabolism were estimated by computer fits using plasma concentration-time profiles as the driving force functions. Results. The CNS delivery of F-ddI did not differ significantly from that for ddI. F-ddA, which is more lipophilic than F-ddI, provided higher brain (≈ 8×) and CSF (≈ 11×) concentrations of total dideoxynucleoside (F-ddA and F-ddI) compared to F-ddI. Deamination by brain tissue ADA to form F-ddI reduced CNS levels of intact F-ddA but provided higher brain parenchyma (5×) and CSF/plasma (3×) ratios of F-ddI relative to F-ddI controls. Thus, F-ddA functions in part as a CNS-activated prodrug of F-ddI. DCF pre-treatment inhibited brain tissue ADA, abolishing the prodrug effect, and enhancing F-ddA concentrations in both brain parenchyma (5×) and CSF (6×). Conclusions. PNP metabolism does not appear to play a role in the low CNS delivery of ddI. On the other hand, deamination of F-ddA by brain tissue ADA is an important process, such that F-ddA functions in part as a CNS-activated prodrug of F-ddI. Enhanced CNS uptake of intact F-ddA can be achieved with ADA inhibition.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1012110724604
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  • 9
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    Mean molecular potentials in a model lipid bilayer: A molecular dynamics simulation (1995)
    American Institute of Physics
    Details
    Publication Date: 1995-11-15
    Print ISSN: 0021-9606
    Electronic ISSN: 1089-7690
    Topics: Chemistry and Pharmacology , Physics
    Published by American Institute of Physics
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  • 10
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    Molecular dissolution processes in lipid bilayers: A molecular dynamics simulation (1999)
    American Institute of Physics
    Details
    Publication Date: 1999-01-15
    Print ISSN: 0021-9606
    Electronic ISSN: 1089-7690
    Topics: Chemistry and Pharmacology , Physics
    Published by American Institute of Physics
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