Defense Date


Document Type


Degree Name

Master of Science


Pharmaceutical Sciences

First Advisor



This research explored quantitative relationships (QSPKR) between different molecular descriptors and pertinent, systemic PK properties for 14 calcium channel blockers (CCB). Physicochemical properties (PC) such as molecular weight (MW), molar volume (MV), calculated logP (clogP), pKa, calculated logD7.4 (clogD), % ionized at pH 6.3 and pH 7.4, hydrogen bond donors (HBD), hydrogen bond acceptors (HBA), and number of rotatable bonds (nRot) were chosen as possible predictor variables for systemic PK properties for CCB, obtained from pertinent literature, assessing the PK of CCB after intravenous administration to healthy humans. All PC properties and molecular descriptors were computed using ACD-solubility/DB 12.01. Total body clearance (CLtot), steady-state volume of distribution (Vdss), total area under the plasma concentration-time profile (AUCoo), terminal half-life (t1/2), and fraction of drug excreted unchanged in urine (fe), if available, were obtained or derived from original references, exclusively from IV studies that administered CCB to healthy human volunteers. Several articles focused on drug interactions with grapefruit juice or the impact of renal/hepatic dysfunction, and in such cases, data from the healthy control group were used. Each study was evaluated for study design, PK sampling schedule, bioanalytical and PK analysis methods before inclusion into the final database. The assumption of linear systemic PK was verified by assessing AUCoo versus (IV) dose. Plasma protein binding information was collected from in-vitro experiments to obtain the fraction unbound in plasma (fu). Unbound volume of distribution at a steady state (Vdssu), unbound total (CLtotu), renal (CLrenu), and non-renal clearance (CLnonrenu) were estimated and compared with the relevant physiological references for Vdssu (plasma volume, blood volume, extracellular and intracellular spaces, total body water and body weight) and for the unbound clearances (liver blood flow, renal plasma flow, and glomerular filtration rate, GFR). Final PK property values were obtained by averaging across available studies. The distribution of both PC and PK properties were evaluated, and correlation matrices amongst PC properties were constructed to assess for collinearity. If two PC descriptors were found to be collinear, i.e. r, ≥ 0.8, only one of them was used in the final univariate analysis. Finally, univariate linear regression of all PK variables versus each molecular descriptor was performed; any relationship with p<0.05 and r2≥0.30 was considered to be statistically significant. The PC properties of the final 14 CCB were reasonably normally distributed with few exceptions. Overall, CCBs are small (MW range of 316-496 Da), basic and lipophilic (logD7.4 range of 1.5-5.1) molecules. On the other hand, for the PK properties, the distributions were found to be skewed with high standard deviations. Thus, all PK variables (except fu) were log-transformed. Although CCB are mostly highly plasma protein bound (fu range of 0.2-20%), they are characterized by extensive extravascular tissue distribution (Vdss range of 0.6-20.4 l/kg) and high, mainly metabolic, clearance (CLtot range of 3.7-131.7 ml/min/kg). Clevidipine is the only CCB undergoing extensive, extra-hepatic ester hydrolysis, responsible for the highest CLtot value. Urinary excretion for CCB is negligible. Amlodipine is a PK outlier due to its high Vdss (20.4 l/kg) and low CLtot (6.9 ml/min/kg, due to low hepatic extraction) with fu of 2%. Therefore, the final QSPKR analysis was performed including, as well as excluding amlodipine. Excluding amlodipine, the relationship between fu and logD7.4 was negative and significant (r2 of 0.4, n=12). The relationships between CLtotu, CLnonrenu and CLrenu and logD7.4 were found to be positive and significant (r2 between 0.6-0.7, n=3-12); none of the other PC variables affected any of the clearance terms. Although the relationship between Vdssu and logD7.4 was not significant (r2 of 0.25, n=12), it showed the expected positive slope. In fact, after removing bepridil (the remaining outlier in Vdssu), the relationship with logD7.4 became statistically significant (r2=0.46, n=11). The QSPKR obtained in this study for CCB, with logD7.4 being the main PC determinant for systemic PK properties, were similar to those previously reported for opioids, β-adrenergic receptor ligands and benzodiazepines. However, slope estimates for the relationships of CLnonrenu and CLtotu as a function of logD7.4 for CCB were higher compared to these previously studied compounds, which showed higher sensitivity, most likely as a result of their higher lipophilicity. Overall, lipophilicity measured as logD7.4 was found to be a statistically significant and plausible PC determinant for the biologically relevant systemic PK properties for CCB and other classes of drugs.


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VCU Theses and Dissertations

Date of Submission

August 2012