Suitable albumin concentrations for enhanced drug oxidation activities mediated by human liver microsomal cytochrome P450 2C9 and other forms predicted with unbound fractions and partition/distribution coefficients of model substrates

1. Albumin has reportedly enhanced cytochrome P450 (P450)-mediated drug oxidation rates in human liver microsomes. Consequently, measurements of clearances and fractions metabolized could vary depending on the experimental albumin concentrations used.

2. In this study, the oxidation rates of diclofenac and warfarin by human liver microsomes were significantly enhanced in the presence of 0.10% (w/v) bovine serum albumin, whereas those of tolbutamide and phenytoin required 1.0% and 2.0% of albumin for significant enhancement. Values of the fractions metabolized by P450 2C9 for four substrates did not markedly change in the presence of albumin at the above-mentioned concentrations.

3. The oxidation rates of bupropion, omeprazole, chlorzoxazone and phenacetin in human liver microsomes were reportedly enhanced by 0.5%, 1%, 2% and 2% of albumin, respectively. Analysis of reported intrinsic clearance values and suitable albumin concentrations for the currently analyzed substrates and the reported substrates revealed an inverse correlation, with warfarin as an outlier.

4. Suitable albumin concentrations were multivariately correlated with physicochemical properties, that is, the plasma unbound fractions, octanol–water partition coefficient and acid dissociation constant (r?=?0.98, p<.0001, n?=?10). Therefore, multiple physicochemical properties may be determinants of suitable albumin concentrations for substrate oxidations in human liver microsomes.

     

甲磺酸地拉韦啶解离常数及分配系数的测定

目的:测定甲磺酸地拉韦啶的解离常数和分配系数。方法:采用酸碱滴定法测定不同体积比的甲醇-水溶液中的药物pKa值,再外推至纯水中药物浓度无限稀释时的pKa值。采用HPLC法测定药物的分配系数。结果:甲磺酸地拉韦啶的pKa为4.635,1gP值为2.907。结论:甲磺酸地拉韦啶为弱酸性亲脂性药物。     

高效液相色谱法测定十一酸睾酮在不同介质中的平衡溶解度和表观油水分配系数

目的测定十一酸睾酮在水和表面活性剂溶液中的平衡溶解度以及在正辛醇-缓冲液体系中的表观油水分配系数。方法采用高效液相色谱法测定十一酸睾酮在水和表面活性剂溶液中的浓度,采用摇瓶法测定十一酸睾酮的表观油水分配系数。结果 37℃下十一酸睾酮在水中不溶,Cremophor EL-35对十一酸睾酮有较强的增溶能力;十一酸睾酮的表观油水分配系数为12.21。结论十一酸睾酮的水溶性差,提高其制剂的溶出度可能会提高其生物利用度。     

A quantitative structure-activity relationship between partition coefficients and the acute toxicity of naphthalene derivatives in Artemia salina nauplii

The 1-octanol/water partition coefficient has been used frequently as a rapid predictor of organic pollutant bioconcentration potential in aquatic life. Harmful effects of aromatic compounds have been related to partition coefficients in a meaningful way. Acute toxicity tests were conducted by exposing 30-h posthatch Artemia salina larvae cultured at 19°C in artificial sea water to naphthalene, naphthalene derivatives, and other nonrelated chemicals for 24 h to determine immobilization concentrations (IC₅₀). The IC₅₀ value for each chemical was used to derive a quantitative structure-activity relationship (QSAR) which included the partition coefficient as the only parameter of molecular structure. A linear correlation resulted for all chemicals tested using Artemia:

$\text{log}\text{1}\text{IC}{}_{50}\text{=1.57(plusm 0.60)+0.88(plusm 0.12)×}\text{log}\text{P}$

where n = 11, r² = 0.968, and s = 0.226. The hydrophobic nature of the chemicals appeared to be the most important factor producing larval immobilization because the naphthalene congener set was not collinear with electronic and steric physicochemical properties. The IC₅₀ values were also correlated with the molecular weight and boiling point of each chemical, but a significant increase in the regression variance occurred in comparison to log P. The naphthalene QSAR was a good predictor of acute toxicity in Artemia nauplii.     

A unified algorithm for predicting partition coefficients for PBPK modeling of drugs and environmental chemicals

The algorithms in the literature focusing to predict tissue:blood PC (P_tb) for environmental chemicals and tissue:plasma PC based on total (K_p) or unbound concentration (K_pu) for drugs differ in their consideration of binding to hemoglobin, plasma proteins and charged phospholipids. The objective of the present study was to develop a unified algorithm such that P_tb, K_p and K_pu for both drugs and environmental chemicals could be predicted. The development of the unified algorithm was accomplished by integrating all mechanistic algorithms previously published to compute the PCs. Furthermore, the algorithm was structured in such a way as to facilitate predictions of the distribution of organic compounds at the macro (i.e. whole tissue) and micro (i.e. cells and fluids) levels. The resulting unified algorithm was applied to compute the rat P_tb, K_p or K_pu of muscle (n = 174), liver (n = 139) and adipose tissue (n = 141) for acidic, neutral, zwitterionic and basic drugs as well as ketones, acetate esters, alcohols, aliphatic hydrocarbons, aromatic hydrocarbons and ethers. The unified algorithm reproduced adequately the values predicted previously by the published algorithms for a total of 142 drugs and chemicals. The sensitivity analysis demonstrated the relative importance of the various compound properties reflective of specific mechanistic determinants relevant to prediction of PC values of drugs and environmental chemicals. Overall, the present unified algorithm uniquely facilitates the computation of macro and micro level PCs for developing organ and cellular-level PBPK models for both chemicals and drugs.