No abstract

In this study, the pharmacokinetics of verapamil and its active metabolite norverapamil were evaluated following intravenous and oral administration of 10 mg/kg verapamil to rats with hyperlipidaemia (HL) induced by poloxamer 407 (HL rats). The total area under the plasma concentration time curve (AUC) of verapamil in HL rats following intravenous administration was significantly greater (by 11.2%) than in control rats due to their slower (by 11%) non-renal clearance. The oral AUC of verapamil in HL rats was also significantly greater (by 116%) compared with controls, with a larger magnitude than the data observed following intravenous administration. This may have been a result of the decreased intestinal metabolism of verapamil in HL rats. The AUC of norverapamil and AUC(norverapamil)/AUC(verapamil) ratios following intravenous and oral administration of verapamil were unchanged in HL rats. Assuming that the HL rat model qualitatively reflects similar changes in patients with HL, the findings of this study have potential therapeutic implications. Further studies in humans are required to determine whether modification of the oral verapamil dosage regimen in HL states is necessary.

Reliably predicting pharmacokinetic behavior in humans from preclinical data is an important aspect of drug development. The most widely used technique in this regard is allometric scaling. In this review, various approaches developed for predicting pharmacokinetic parameters in humans using interspecies scaling are introduced and discussed. Methods to predict plasma concentration-time profiles in humans after intravenous and oral administration are also reviewed. The reliable prediction of human pharmacokinetics with regard to investigational drugs is aimed, ultimately, at selecting the first in-human dose with which to begin clinical studies. Approaches for the selection of the first in-human dose are also reviewed. Although there have been many trials to compare and optimize interspecies scaling methods, no firm conclusions have been reached. Because interspecies scaling methods are still highly empirical, further effort is needed to improve the reliability of predicting human pharmacokinetics by interspecies scaling.