Effect of lyophilized grapefruit juice on P-glycoprotein-mediated drug transport in-vitro and in-vivo.

The administration of grapefruit juice (GFJ) has been postulated to inhibit the activity of P-glycoprotein (P-gp) transport system and thus can enhance the uptake of substrate drugs. However, for various reasons, the results obtained have been always swaying between confirmation and refutation. This study aims at re-evaluating the effect of lyophilized freshly-prepared grapefruit juice (LGFJ) prepared from the whole peeled fruit on P-gp activity using the model drug doxorubicin (DOX) in-vitro and timolol maleate (TM) in-vivo. Human uterine sarcoma MES-SA/DX5v cells, grown under nanomolar concentration of DOX and highly expressing P-gp, were used as model cells for in-vitro studies whereas white New Zealand male rabbits were used for in-vivo studies. Results showed that the accumulation of DOX in MES-SA/DX5v cells was increased by 18.3 ± 2.0% in presence of LGFJ compared to control experiments. Results from in-vivo absorption studies showed that the relative oral bioavailability of TM ingested with LGFJ was significantly higher by 70% and 43% compared to the oral bioavailability of TM ingested with saline and a commercial GFJ, respectively. This study as such confirms the inhibitory effects of LGFJ on P-gp efflux proteins and highlights the superiority of using lyophilized freshly prepared juices over the commercially available juices in research studies. Also, the results call for further studies to assess the possibility of co-administrating LGFJ with anti-cancer agents to modulate multidrug resistance in their cellular environment or incorporating LGFJ in solid dosage forms to improve oral bioavailability of drugs.

Comparison of in vitro and in vivo performance of a colonic delivery system.

The aim of this work is to compare in vitro to in vivo performance of a colonic drug delivery system, made of small pectin-ethylcellulose coated drug beads. The delivery system was evaluated in vitro by conducting drug release studies in different dissolution media to mimic transit times and pH conditions in the stomach, small intestine and colon and in vivo by using gamma-scintigraphic studies in dogs and absorption studies in human volunteers under fed and fasted conditions. In vitro release studies indicated that drug release rate depended on the ratio of the pectin to ethylcellulose in the coat and the thickness of the coat. In vivo release studies obtained by deconvolution of biostudy data did not correlate with in vitro results obtained from most coat formulations. Beads showing ideal release profiles in vitro showed very poor performance in vivo and only those beads showing colonic premature drug release in vitro might be able to deliver the drug to the colon. Scintigraphic studies of a selected formulation showed that the labeled beads had an estimated gastric emptying time of 3 h, an estimated small intestine transit time of 2 h and an estimated colonic transit time of 36 h. Average in vivo lag times of the selected formulation from absorption studies in humans were found to be 6.1 h and 4.8 h under fed and fasted conditions, respectively. The C(max) was also observed at 6.8 h and 5.5 h on average, under fed and fasted conditions, respectively, which might indicate that release of drug from the beads, resulted from degradation of pectin in the coat by enzymatic action in the colon rather than by simple diffusion. Deconvolution of biostudy data showed that drug absorption continued on average for at least 12 h under both fed and fasted conditions.