The influence of three kinetic variables – absorption rate, lipid solubiltty and elimination half-tife – on abuse and dependence potential were tested as follows.
Absorption rate (expressed as time to peak plasma concentrations) was postulated to be inversely correlated to abuse risk. Therefore, absorption rates of different benzodiazepines were obtained from the literature and used to estimate the abuse risk rank for each drug from 1 (highest abuse risk) to 10 (lowest abuse risk). In cases where absorption rates differed among publications, the mean of all available absorption rates was used. For benzodiazepines that are pro-drugs(eg, clo-razepate, flurazepam), the rate of appearance of the main metabolite was used for the ranking. A specific example of how the ranking was done is shown in Figure 1. Buy Asthma Inhalers Online
Lipid solubility (expressed as high performance liquid chromatography [hplc] retention time) was postulated to be directly associated with rate of brain entry and abuse risk and ranked as explained above for absorption rate.
Elimination half-life was postulated to be related to dependence risk in a nonlinear relationship giving higher dependence liability to benzodiazepines with intermediate elimination half-life. Thus, the risk rankings of benzodiazepines with short half-tife (less than 10 h) were re-ranked.
Figure 1) Postulated relationship between absorption rate and abuse risk. Flurazepam (mean time to peak plasma levels of desalkylfluraze-pam = 10.6^3 h, abuse risk = 10) is not shown so the values for the other nine benzodiazepines can be seen but it has been included in the calculations. DMDZ Desmethyldiazepam