Prediction of Biliary Excretion in Rats and Humans Using Molecular Weight and Quantitative Structure–Pharmacokinetic Relationships

Abstract

Abstract. The aims were (1) to evaluate the molecular weight (MW) dependence of biliary excretion and (2) to develop quantitative structure-pharmacokinetic relationships (QSPKR) to predict biliary clearance (CL b ) and percentage of administered dose excreted in bile as parent drug (PD b ) in rats and humans. CL b and PD b data were collected from the literature for rats and humans. Receiver operating characteristic curve analysis was utilized to determine whether a MW threshold exists for PD b . Stepwise multiple linear regression (MLR) was used to derive QSPKR models. The predictive performance of the models was evaluated by internal validation using the leave-one-out method and external test groups. A MW threshold of 400 Da was determined for PD b for anions in rats, while 475 Da was the cutoff for anions in humans. MW thresholds were not present for cations or cations/neutral compounds in either rats or humans. The QSPKR model for human CL b showed a significant correlation (R 2 =0.819) with good prediction performance (Q 2 =0.722). The model was further assessed using a test group, yielding a geometric mean fold-error of 2.68. QSPKR models with significant correlation and good predictability were also developed for CL b in rats and PD b data for anions or cation/neutral compounds in rats and humans. Both CL b and PD b data were further evaluated for subsets of MRP2 or P-glycoprotein substrates, and significant relationships were derived. QSPKR models were successfully developed for biliary excretion of non-congeneric compounds in rats and humans, providing a quantitative prediction of biliary clearance of compounds.

Disposition of the Emerging Brominated Flame Retardant, 2-Ethylhexyl 2,3,4,5-Tetrabromobenzoate, in Female SD Rats and Male B6C3F1 Mice: Effects of Dose, Route, and Repeated Administration

“…Free TBBA-sulfate might be expected to be cleared via bile, as the biliary molecular weight cutoff in rats is approx. 400 Da (Yang et al, 2009). Similarly, glycine conjugated TBBA (molecular weight 494.7) appeared to be almost entirely eliminated in urine, indicating it too adsorbs to urinary proteins.…”

Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

“…Although historically biliary excretion was predicted for high molecular weight anionic drugs (26,27), segregating drugs into ionization classes provided somewhat better performance of MW as a predictor of excretion class for cationic, neutral and zwitterionic compounds compared to anionic compounds (Table II).…”

“…Their study and others implicated hydrogen bond interactions (5,27), charge state (5,27,28), the presence of polar groups or a large polar surface area (5,(27)(28)(29)(30), and the presence of dipole or quadrupole moments (27,28), while others have implicated hydrophilicity (5,28,30), carboxylic acid groups (28,29), and rotatable bonds (5,29).…”

“…Recently, Yang et al published a model including 97 drugs, which as a part predicted that anionic drugs with molecular weights greater than 475 Da are likely to be significantly (>10% of parent dose) excreted in the bile (27).…”

Prevention of Contrast Medium Induced Nephropathy by Liposome Encapsulation

“…Generally, only drugs (and metabolite) with a molecular weight of > 300 g/mole and with both polar and lipophilic groups are more likely to be excreted in bile [23]. We found that the presence of liposome had influence on the distribution of CM excretion routes indicated by the signal increase in bladder (waste storage of renal excretion) and intestine (waste storage of biliary excretion) as shown in Fig.…”