Disposition of acetaminophen and indocyanine green in cystic fibrosis-knockout mice
Journal Title: The AAPS Journal - Year 2000, Vol 2, Issue 2
Abstract
Drug treatment poses a therapeutic challenge in cystic fibrosis (CF) because the disposition of a number of drugs is altered in CF. Enhanced clearance of acetaminophen (APAP) and indocyanine green (ICG) have previously been reported in CF patients. The objective of the current study was to investigate if the CF-knockout mouse model (cftrm1UNC) shows altered pharmacokinetics similar to those seen in CF patients using the 2 model compounds APAP and ICG. Clearance (CL/F) of APAP and renal (CLR) and formation (CLf) clearance of acetaminophen glucuronide (AG) and acetaminophen sulfate (AS) were determined in CF-knockout mice following administration of APAP (50 mg/kg, intraperitoneal). CLR of AS was 19.5 and 12.9 (mL/min per kg) and CLf of AS was 10.4 and 6.7 mL/min per kg for homozygous and heterozygous males, respectively, which was significantly different between groups. CLR of AG was 6.3 and 4.8 mL/min per kg and CLf of AG was 9.6 and 8.9 mL/min per kg for homozygous and heterozygous males, respectively, although not reaching statistical significance. No significant differences were noted in either ClR or CLf of AG and AS in female CF mice. Plasma concentrations of ICG (10 mg/kg, intravenous) were determined over 0 to 15 minutes. Homozygous females showed a higher apparent volume of distribution (96 mL/kg) relative to heterozygous females (72 mL/kg). Similar to CF patients, a trend toward a lower Cmax was noted in homozygous male and female mice. However, contrary to human data, no significant differences in CL of ICG were noted. These results suggest that the CF-knockout mice have potential as a model for studying altered drug disposition in CF patients.
Authors and Affiliations
Swarupa G. Kulkarni, Anita A. Pegram, Philip C. Smith
Keywords
Related Articles
- EP ID EP682091
- DOI 10.1208/ps020218
- Views 71
- Downloads 0
Prediction of Human Glomerular Filtration Rate from Preterm Neonates to Adults: Evaluation of Predictive Performance of Several Empirical Models
The objective of this study was to evaluate the predictive performance of several allometric empirical models (body weight dependent, age dependent, fixed exponent 0.75, a data-dependent single exponent, and maturation m...
Modeling of Bounded Outcome Scores with Data on the Boundaries: Application to Disability Assessment for Dementia Scores in Alzheimer’s Disease
The online version of this article (doi:10.1208/s12248-014-9655-y) contains supplementary material, which is available to authorized users.
Pharmacokinetic Interaction between the Flavonoid Luteolin and γ-Hydroxybutyrate in Rats: Potential Involvement of Monocarboxylate Transporters
Monocarboxylate transporter 1 (MCT1) has been previously reported as an important determinant of the renal reabsorption of the drug of abuse, γ-hydroxybutyrate (GHB). Luteolin is a potent MCT1 inhibitor, inhibiti...
Species and Gender Differences Affect the Metabolism of Emodin via Glucuronidation
The aim of the present study was to define the mechanisms responsible for poor bioavailability of emodin by determining its metabolism using in vitro and in situ disposition models of the intestine and liver. Liver micro...
Development and Advanced Validation of an Optimized Method for the Quantitation of Aβ42 in Human Cerebrospinal Fluid
The online version of this article (doi:10.1208/s12248-012-9360-7) contains supplementary material, which is available to authorized users.