Quantitative Structure Pharmacokinetic Relationship Studies for Drug Clearance of Quinolone Drugs Paul Yash1, Dhake Avinash S.2, Parle Milind3, Singh Bhupinder4,* 1Lord Shiva College of Pharmacy, Sirsa (Haryana), India 2L.B. Rao Institute of Pharm. Education and Research, Anand, Gujarat, India 3Guru Jambheshwar University of Science & Technology, Hisar (Haryana), India 4Univ. Institute of Pharm. Sciences, Panjab University, Chandigarh, India *Corresponding Author E-mail: bsbhoop@yahoo.com
Abstract Quantitative Structure Pharmacokinetic Relationships (QSPR) studies tend not only to establish the quantitative relationships between structural properties and the pharmacokinetic parameters of new compounds, but also provide great help for better elucidation of factors influencing the pharmacokinetic fate of drugs. Clearance (CLtot) value is one of the most imperative pharmacokinetic parameters related directly to dispositional characteristics of drug(s). It can be used to determine the dosing rate and steady state concentration of a drug in clinical pharmacokinetics. The current study was conducted to investigate QSPR for CLtot values in man amongst 24 quinolone drugs employing extrathermodynamic approach. Analysis of several hundreds of QSPR correlations developed in the current study revealed extremely high degree of cross-validated coefficients (Q2) using leave-one-out (LOO) method (p<0.001). CLtot shows positive liner dependence on topological parameters (e.g., BLI and negative liner dependence on electrostatic parameters (e.g., Qmax, QOmax, Qmax-Qmin). Influences of lipophilic parameters like log P, geometrical parameters like ZXS/ZXR and constitutional parameters like Cn and Brel was also noticed during multi-parameter studies. The joint dependence of clearance values on topological and electro parameters signifies the importance of diffusion and ionization of quinolones drugs in vivo. The overall predictability was found to be quite high (R2=0.9132, F=26.78, S2=6.72, Q2=0.7256, p<0.001). Logarithmic transformation of clearance did not yield much improvement in the significance of correlations, but the inverse transforms showed improved correlation (R2=0.9332, F=34.52, S2=0.0014, Q2=0.8136, p<0.001). Top Keywords Quantitative structure pharmacokinetic relationships (QSPR), clearance, ADME. Top |