caa a22 4500 477126944 CHVBK 20180405111652.0 cr unu---uuuuu 170330e19970301xx s 000 0 eng 10.1023/A:1012002206007 doi (NATIONALLICENCE)springer-10.1023/A:1012002206007 Physiologically Based Pharmacokinetic Models of 2′,3′-Dideoxyinosine [Elektronische Daten] [Hyo-Jeong Kang, M. Wientjes, Jessie Au] Purpose. The goal of this study was to develop physiologically based pharmacokinetic (PBPK) models for 2′,3′-dideoxyinosine (ddI) in rats when the drug was administered alone (ddI model) and with pentamidine (ddI + pentamidine model), and to use these models to evaluate the effect of our previously reported pentamidine-ddI interaction on tissue ddI exposure in humans. Methods. The PBPK models consisted of pharmacologically relevant tissues (blood, brain, gut, spleen, pancreas, liver, kidney, lymph nodes, muscle) and used the assumptions of perfusion-rate limited tissue distribution and linear tissue binding of ddI. The required physiologic model parameters were obtained from the literature, whereas the pharmacokinetic parameters and the tissue-to-plasma partition coefficients were calculated using plasma and tissue data. Results. The ddI model in rats yielded model-predicted concentration-time profiles that were in close agreement with the experimentally determined profiles after an intravenous ddI dose (5% deviation in plasma and 20% deviation in tissues). The ddI + pentamidine model incorporated the pentamidine-induced increases of ddI partition in pancreas and muscle. The two PBPK models were scaled-up to humans using human physiologic and pharmacokinetic parameters. A comparison of the model-predicted plasma concentration-time profiles with the observed profiles in AIDS patients who often received ddI with pentamidine showed that the ddI model underestimated the terminal half-life (t1/2,β) by 39% whereas the ddI + pentamidine model yielded identical t1/2,β and area-under-the-curve as the observed values (<1% deviation). Simulations of ddI concentration-time profiles in human tissues using the two models showed that pancreas and lymph nodes received about 2- to 30-fold higher ddI concentration than spleen and brain, and that coadministration of pentamidine increased the AUC of ddl in the pancreas by 20%. Conclusions. Data of the present study indicate that the plasma ddI concentration-time profile in patients were better described by the ddI + pentamidine model than by the ddI model, suggesting that the pentamidine-induced changes in tissue distribution of ddI observed in rats may also occur in humans. Plenum Publishing Corporation, 1997 ddI nationallicence physiologic pharmacokinetic model nationallicence tissue concentration nationallicence pentamidine nationallicence rat nationallicence human nationallicence Kang Hyo-Jeong College of Pharmacy, The Ohio State University, 500 West 12th Avenue, 43210, Columbus, Ohio aut Wientjes M. College of Pharmacy, The Ohio State University, 500 West 12th Avenue, 43210, Columbus, Ohio aut Au Jessie Division of Urology, College of Medicine, The Ohio State University, 43210, Columbus, Ohio aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/3(1997-03-01), 337-344 0724-8741 14:3<337 1997 14 11095 https://doi.org/10.1023/A:1012002206007 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012002206007 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kang Hyo-Jeong College of Pharmacy, The Ohio State University, 500 West 12th Avenue, 43210, Columbus, Ohio aut NATIONALLICENCE 700 1- Wientjes M. College of Pharmacy, The Ohio State University, 500 West 12th Avenue, 43210, Columbus, Ohio aut NATIONALLICENCE 700 1- Au Jessie Division of Urology, College of Medicine, The Ohio State University, 43210, Columbus, Ohio aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/3(1997-03-01), 337-344 0724-8741 14:3<337 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer