Pharmacokinetics and Physiologically Based Pharmacokinetic Modeling of Xenobiotic Disposition in Special Populations
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Due to the alteration of the physiological functions, the disposition of xenobiotics is often changed under disease conditions and during pregnancy compared with the healthy status. Under disease conditions including chronic kidney disease (CKD) and cancer, altered physiological functions including changes in liver and kidney function have critical impact on the pharmacokinetics of xenobiotics. During pregnancy, the changes in organ blood flow, plasma protein binding and the expression of hepatic drug metabolizing enzymes can also affect the intrinsic capacity of the organ to metabolize and excrete xenobiotic. However, little is known on the disposition of vitamin A and its metabolites including all-trans retinoic acid (atRA) in CKD and cancer patients and the disposition of domoic acid (DA), a shellfish toxin, during pregnancy. The aims of the thesis project is to better characterize the disposition of retinoids in CKD and cancer patients, evaluate the disposition of DA before and during pregnancy in non-human primates and utilize the obtained in vitro and in vivo information to develop physiologically based pharmacokinetic (PBPK) model to simulate the disposition of atRA and DA. To evaluate the disposition of endogenous retinoids and their carrier proteins in CKD patients in comparison to healthy subjects, retinoids and their carrier proteins such as retinol binding protein (RBP4) concentrations in plasma and urine from 55 adult CKD patients and 21 matched healthy subjects were measured. RBP4 and retinol levels were increased approximately 2-fold in patients with CKD. RBP4 renal clearance was higher in patients with CKD than healthy subjects but not associated with estimated glomerular filtration rate (eGFR). Circulating concentrations of atRA increased and concentrations of 13cisRA decreased in subjects with CKD with no change in RA-to-retinol ratio. Increases in circulating retinol, RBP4, and atRA may be due to increased hepatic RBP4 synthesis, retinyl ester hydrolysis, and/or hepatic secretion of RBP4-retinol. To better characterize and understand the disposition of therapeutically administered atRA in healthy and cancer patients in the presence and absence of inhibitors of atRA metabolism, a population based PBPK model of atRA disposition incorporated saturable metabolic clearance of atRA, induction of CYP26A1 by atRA and the absorption and distribution kinetics of atRA was developed and verified using in vitro and in vivo data. The developed model can be used for the interpretation of atRA disposition and efficacy, design of novel dosing strategies, and development of next-generation atRA metabolism inhibitors. To investigate the disposition of DA, toxicokinetics of DA were characterized in female cynomolgus monkeys, following a single 5 µg/kg IV bolus dose and single 0.075 mg/kg and 0.15 mg/kg PO dose before pregnancy. Following IV dosing, DA had a distribution volume of 145 ± 69 ml/kg, systemic clearance of 139 ± 70 ml/hr/kg and elimination half-life of 1.4 ± 1.0 hours. However, following PO dosing, the average terminal half-life of DA was 11± 3.7 hours, indicating that after PO administration DA disposition follows flip-flop kinetics with slow rate-limiting absorption. The absolute bioavailability of DA was 7 ± 4 %. DA was primarily renally eliminated with renal clearance of 104 ± 47 ml/hr/kg. The developed DA PBPK model in monkeys simulated the flip-flop kinetics observed after oral administration and allowed the simulation of urinary excretion and brain and kidney distribution of DA, following IV and PO dosing. DA toxicokinetics were further characterized in monkeys during pregnancy following chronic dose of 0.15 mg/kg/day DA. Decreased AUC of DA and increased DA renal clearance were observed during pregnancy. DA was detected in both plasma and urine samples of delivered infants.
- Pharmaceutics