In Silico Docking of Alkylphosphocholine Analogs to Human Serum Albumin Predicts Partitioning and Pharmacokinetics.

Alkylphosphocholine (APC) analogs are a novel class of broad-spectrum tumor-targeting agents that can be used for both diagnosis and treatment of cancer. The potential for clinical translation for APC analogs will strongly depend on their pharmacokinetic (PK) profiles. The aim of this work was to understand how the chemical structures of various APC analogs impact binding and PK. To achieve this aim, we performed in silico docking analysis, in vitro and in vivo partitioning experiments, and in vivo PK studies. Our results have identified 7 potential high-affinity binding sites of these compounds on human serum albumin (HSA) and suggest that the size of the functional group directly influences the albumin binding, partitioning, and PK. Namely, the bulkier the functional groups, the weaker the agent binds to albumin, the more the agent partitions onto lipoproteins, and the less time the agent spends in circulation. The results of these experiments provide novel molecular insights into the binding, partitioning, and PK of this class of compounds and similar molecules as well as suggest pharmacological strategies to alter their PK profiles. Importantly, our methodology may provide a way to design better drugs by better characterizing the PK profile for lead compound optimization.

Plasma clearance and half-life of prostaglandin F2alpha: a comparison between mares and heifers.

Horses are about five times more sensitive to the luteolytic effect of prostaglandin F2alpha (PGF) than cattle, as indicated by a recommended clinical dose of 5 mg in horses and 25 mg in cattle. Novel evaluations of the PGF plasma disappearance curves were made in mares and in heifers, and the two species were compared. Mares and heifers (n = 5) of similar body weight were injected (Min 0) intravenously with PGF (5 mg per animal). Blood was sampled every 10 sec until Min 3, every 30 sec until Min 5, every 10 min until Min 60, and every 30 min until Min 240. The mean PGF concentration was greater (P < 0.05) in mares than in heifers at Min 1 through Min 60 and at Mins 180 and 240. The mean time to maximum PGF concentration was not different between mares (42.0 ± 8.6 sec) and heifers (35.0 ± 2.9 sec). The apparent plasma clearance, distribution half-life, elimination half-life, and maximum plasma PGF concentration were 3.3 ± 0.5 L h(-1) kg(-1), 94.2 ± 15.9 sec, 25.9 ± 5.0 min, and 249.1 ± 36.8 ng/ml, respectively, in mares and 15.4 ± 2.3 L h(-1) kg(-1), 29.2 ± 3.9 sec, 9.0 ± 0.9 min, and 51.4 ± 22.6 ng/ml, respectively, in heifers. Plasma clearance was about five times less (P < 0.0005), maximum plasma PGF concentration was five times greater (P < 0.002), and the distribution half-life and elimination half-life were about three times longer (P < 0.005) in mares than in heifers. The fivefold greater plasma clearance of PGF in heifers than in mares corresponds to the recommended fivefold greater clinical dose of PGF in cattle and supported the hypothesis that the metabolic clearance of PGF is slower in mares than heifers.

Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT.

We have previously developed a model that provides relative dosimetry estimates for targeted radionuclide therapy (TRT) agents. The whole-body and tumor pharmacokinetic (PK) parameters of this model can be noninvasively measured with molecular imaging, providing a means of comparing potential TRT agents. Parameter sensitivities and noise will affect the accuracy and precision of the estimated PK values and hence dosimetry estimates. The aim of this work is to apply a PK model for TRT to two agents with different magnitudes of clearance rates, NM404 and FLT, explore parameter sensitivity with respect to time and investigate the effect of noise on parameter precision and accuracy. Twenty-three tumor bearing mice were injected with a 'slow-clearing' agent, (124)I-NM404 (n = 10), or a 'fast-clearing' agent, (18)F-FLT (3'-deoxy-3'-fluorothymidine) (n = 13) and imaged via micro-PET/CT pseudo-dynamically or dynamically, respectively. Regions of interest were drawn within the heart and tumor to create time-concentration curves for blood pool and tumor. PK analysis was performed to estimate the mean and standard error of the central compartment efflux-to-influx ratio (k(12)/k(21)), central elimination rate constant (k(el)), and tumor influx-to-efflux ratio (k(34)/k(43)), as well as the mean and standard deviation of the dosimetry estimates. NM404 and FLT parameter estimation results were used to analyze model accuracy and parameter sensitivity. The accuracy of the experimental sampling schedule was compared to that of an optimal sampling schedule found using Cramer-Rao lower bounds theory. Accuracy was assessed using correlation coefficient, bias and standard error of the estimate normalized to the mean (SEE/mean). The PK parameter estimation of NM404 yielded a central clearance, k(el) (0.009 ± 0.003 h(-1)), normal body retention, k(12)/k(21) (0.69 ± 0.16), tumor retention, k(34)/k(43) (1.44 ± 0.46) and predicted dosimetry, D(tumor) (3.47 ± 1.24 Gy). The PK parameter estimation of FLT yielded a central elimination rate constant, k(el) (0.050 ± 0.025 min(-1)), normal body retention, k(12)/k(21) (2.21 ± 0.62) and tumor retention, k(34)/k(43) (0.65 ± 0.17), and predicted dosimetry, D(tumor) (0.61 ± 0.20 Gy). Compared to experimental sampling, optimal sampling decreases the dosimetry bias and SEE/mean for NM404; however, it increases bias and decreases SEE/mean for FLT. For both NM404 and FLT, central compartment efflux rate constant, k(12), and central compartment influx rate constant, k(21), possess mirroring sensitivities at relatively early time points. The instantaneous concentration in the blood, C(0), was most sensitive at early time points; central elimination, k(el), and tumor efflux, k(43), are most sensitive at later time points. A PK model for TRT was applied to both a slow-clearing, NM404, and a fast-clearing, FLT, agents in a xenograft murine model. NM404 possesses more favorable PK values according to the PK TRT model. The precise and accurate measurement of k(12), k(21), k(el), k(34) and k(43) will translate into improved and precise dosimetry estimations. This work will guide the future use of this PK model for assessing the relative effectiveness of potential TRT agents.

Dosimetric effectiveness of targeted radionuclide therapy based on a pharmacokinetic landscape.

Assessment of targeted radionuclide therapy (TRT) agent effectiveness based on its pharmacokinetic (PK) properties could provide means to expedited agent development or its rejection. A broad PK model that predicts the relative effectiveness of TRT agents based on the relationship between their normal body (k(12), k(21)) and tumor (k(34), k(43)) PK parameters has been developed. A classic two-compartment open model decoupled from a tumor was used to represent the body. Analytically solved differential equations were used to develop a relationship that predicts TRT effectiveness. Various PK scenarios were created by pairing normal body PK parameters of 38 pharmaceuticals found in the literature with estimated tumor PK parameters. Each PK scenario resulted in a maximum permissible injected activity that limited the whole-body dose to 2 Gy and yielded a maximum delivered tumor dose. The model suggests that a k(34):k(43) ratio greater than 5 and a k(12):k(21) ratio less than 1 is effective at delivering doses that ensure sufficient solid tumor control. It was also shown that there is no direct relationship between tumor dose and acid dissociation constant (pK(a)), lipophilicity (log P), and fraction unbound (fu), which are important physicochemical properties. This study suggests that although effective TRT may be difficult to achieve for solid tumors, good TRT agents must have extremely desirable normal body PKs in conjunction with very high tumor retention. The developed PK TRT model could serve as a tool to compare the relative dosimetric effectiveness of existing TRT agents and novel TRT agents early in the developmental phase to potentially reject those that possess unfavorable PKs.

(µ-1,4,7,10-Tetra-oxacyclo-dodeca-ne)bis-[(1,4,7,10-tetra-oxacyclo-dodeca-ne)lithium] bis-(perchlorate).

12-Crown-4 ether (12C4) and LiClO(4) combine to form the ionic title compound, [Li(2)(C(8)H(16)O(4))(3)](ClO(4))(2), which is com-posed of discrete Li/12C4 cations and perchlorate anions. In the [Li(2)(12C4)(3)](2+) cation there are two peripheral 12C4 ligands, which each form four Li-O bonds with only one Li(+) atom. Additionally there is a central 12C4 in which diagonal O atoms form one Li-O bond each with both Li(+) atoms. Therefore each Li(+) atom is penta-coordinated in a distorted square-pyramidal geometry, forming four longer bonds to the O atoms on the peripheral 12C4 and one shorter bond to an O atom of the central 12C4. The cation occupies a crystallographic inversion centre located at the center of the ring of the central 12C4 ligand. The Li(+) atom lies above the cavity of the peripheral 12C4 by 0.815 (2) Šbecause it is too large to fit in the cavity.

(1,4,7,10-Tetra-oxacyclo-dodeca-ne)(trideuteroacetonitrile)lithium perchlorate.

In the title compound, [Li(C(8)H(16)O(4))(CD(3)CN)]ClO(4), the Li atom is penta-coordinate. The O atoms of the 12-crown-4 ether form the basal plane, whereas the N atom of the trideutero-aceto-nitrile occupies the apical position. The Li(+) atom is displaced by 0.794 (6) Štoward the apical position from the plane formed by the O atoms because the Li(+) atom is too large to fit in the cavity of the 12-crown-4 ether, resulting in a distorted square-pyramidal geometry about the Li(+) atom.

(4,7,13,16,21,24-Hexaoxa-1,10-diaza-bicyclo-[8.8.8]hexa-cosa-ne)sodium perchlorate.

The title compound, [Na(C(18)H(36)N(2)O(6))]ClO(4), was isolated and crystallized to understand more fully the ligand's binding specificity to cations. The cation and anion reside at an inter-section of crystallographic twofold and threefold axes. The carbon atoms in the cation are disordered over two positions in a 3:2 ratio, and the anion is equally disordered over two positions. The geometries of the cation and anion are typical. The compound packs in alternating sheets of discrete cations and anions stacked along the c axis, separated by a distance equal to one-sixth the length of the c axis.

First principles investigation of noncovalent complexation: a [2.2.2]-cryptand ion-binding selectivity study.

A first principles methodology, aimed at understanding the roles of molecular conformation and energetics in host-guest binding interactions, is developed and tested on a system that pushes the practical limits of ab initio methods. The binding behavior between the [2.2.2]-cryptand host (4,7,13,16,21,24-hexaoxa-1,10-diaza-bicyclo[8.8.8]hexacosane) and alkali metal cations (Li(+), Na(+), and K(+)) in gas, water, methanol, and acetonitrile is characterized. Hartree-Fock and density functional theory methods are used in concert with crystallographic information to identify gas phase, energy-minimized conformations. Gas phase free energies of binding, with vibrational contributions, are compared to solution-state binding constants through relative binding selectivity analysis. Calculated relative binding free energies qualitatively correlated with solution state experiments only after gas phase metal desolvation is considered. The B3LYP exchange-correlation functional improves theoretical correlations with experimental relative binding free energies. The relevance of gas phase calculations towards understanding binding in condensed phases is discussed. Natural bond orbital methods highlights previously unidentified intramolecular and intermolecular M(+)(222) chemistries, such as an intramolecular n'(O)-->sigma*(CH) hydrogen bond.

Low-temperature enantiotropic k2 phase transition in the ionic 222-cryptand complex with LiClO4.

Crystallographic analyses at 100 and 200 K are reported for the macrobicyclic polyether 4,7,13,16,21,24-hexaoxa-1,10-diaza-bicyclo[8.8.8]hexacosane (denoted as 222-cryptand) that encapsulates a Li+ cation and then forms a complex (I) with ClO4-. Compound (I) undergoes a reversible second-order k phase transition at 253 (2) K from an almost ordered structure [space group P2(1)2(1)2(1)] at 100 K to a more disordered structure that exhibits a different unit cell [P2(1)2(1)2 (2c'=c)] above 253 (2) K. At 295 K the Li+ cation and five atoms of the perchlorate anion are each disordered over at least two positions about a crystallographic twofold axis [Chekhlov (2003). Russ. J. Coord. Chem. 29, 828-832]; as the temperature decreases the dynamic positional disorder is slowly frozen out, but is still observed for lithium even at 100 K. Based upon DFT computations, it seems that in the solid state the position of the Li+ cation in the cavity of the 222-cryptand below 253 (2) K likely corresponds to a local energy minimum; the global minimum in the gas phase corresponds to a near D3 symmetrical conformation of the 222-cryptand with the undersized Li+ cation residing in the center of its cavity.

Determination of the conformation of 2-hydroxy- and 2-aminobenzoic acid dimers using 13C NMR and density functional theory/natural bond order analysis: the central importance of the carboxylic acid carbon.

The 13C chemical shift for the carboxylic acid carbon provides a powerful diagnostic probe to determine the preferred isomeric dimer structures of benzoic acid derivatives undergoing intra- and intermolecular H-bonding in the gas, solution and crystalline phases. We have employed hybrid density functional calculations and natural bond orbital analysis to elucidate the electronic origins of the observed 13C shieldings and their relationship to isomeric stability. We find that delocalizing interactions from the carbonyl oxygen lone pairs (nO) into vicinal carbon-oxygen and carbon-carbon antibonds (sigmaCO*,sigmaCC*) make critical contributions to the 13C shieldings, and these nO --> sigmaCO*, nO --> sigmaCC* interactions are in turn sensitive to the intramolecular interactions that dictate dimer structure and stability. The carboxyl carbon atom can thus serve as a useful detector of subtle structural and conformational features in this pharmacologically important class of carboxylic acid interactions.