Pharmacokinetic modeling and prediction of plasma pyrrole-imidazole polyamide concentration in rats using simultaneous urinary and biliary excretion data.
The use of urinary and/or biliary excretion data was considered as an alternative approach if the bioanalytical method lacked the appropriate sensitivity to adequately characterize the serum or plasma concentration-time profile. This approach is used for the analysis of plasma concentration-time profile under the lower limit of quantification (LLOQ) of various analytical instruments. The objective of this study was to develop a pharmacokinetic (PK) model that describes the plasma concentration-time profiles under LLOQ of HPLC using urinary and biliary excretion data. As model compounds, pyrrole (Py)-imidazole (Im) polyamides 1035 (MW, 1035.12) and 1666 (MW, 1665.78) were used. The cumulative urinary excretions of Py-Im polyamides 1035 and 1666 were 72.4+/-11.6 and 4.8+/-0.5% of the administered dose, respectively. The cumulative biliary excretion of Py-Im polyamide 1035 was 4.3+/-0.4% of the administered dose, and Py-Im polyamide 1666 was not detected. The plasma concentration-time profiles of Py-Im polyamide 1035 were adequately described using linear and non-linear output compartments. The developed PK model could be used to describe the plasma concentration profiles using the linear output compartment interpreted as the urine compartment and the non-linear output compartment interpreted as the bile compartment. This PK model will be able to provide a more accurate prediction of the plasma concentration profiles under LLOQ.
Department of Clinical Pharmacokinetics, College of Pharmacy, Nihon University, Funabashi, Chiba, Japan.
Takashi
T
Nagashima
Takahiko
T
Aoyama
Tsubasa
T
Yokoe
Akiko
A
Fukasawa
Noboru
N
Fukuda
Takahiro
T
Ueno
Hiroshi
H
Sugiyama
Hiroki
H
Nagase
Yoshiaki
Y
Matsumoto
D000818:Animals; D001646:Bile / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007093:Imidazoles / Q000032:analysis / Q000097:blood* / Q000652:urine; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D009757:Nylons / Q000737:chemistry / Q000493:pharmacokinetics*; D011237:Predictive Value of Tests; D011758:Pyrroles / Q000032:analysis / Q000097:blood* / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D014556:Urine / Q000737:chemistry*
D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles