Disposition of acetaminophen and indocyanine green in cystic fibrosis-knockout mice

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 (cftr m1UNC ) 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 (CL R ) and formation (CL f ) clearance of acetaminophen glucuronide (AG) and acetaminophen sulfate (AS) were determined in CFknockout mice following administration of APAP (50 mg/kg, intraperitoneal). CL R of AS was 19.5 and 12.9 (mL/min per kg) and CL f of AS was 10.4 and 6.7 mL/min per kg for homozygous and heterozygous males, respectively, which was significantly different between groups. CL R of AG was 6.3 and 4.8 mL/min per kg and CL f 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 Cl R or CL f 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

Indocyanine green clearance varies as a function of N-acetylcysteine treatment in a murine model of acetaminophen toxicity

“…The clearance of ICG has been previously examined as a functional marker in experimental models of liver injury or toxicity [12,13,27–29]. Inage et al [6] examined the pharmacokinetics of ICG in rats with partial hepatectomy and in rats with fibrosis secondary to carbon tetrachloride toxicity and found that the clearance of ICG correlated with the functional reserve and liver mass [6].…”

“…The method was adapted from Kulkarni et al [12] and validated in our laboratory. A Waters C 18 symmetry column equipped with a guard column (Waters Associates, Milford, MA) was used for reverse-phase chromatography at a temperature of 35° C. The mobile phase consisted of 50 mM potassium phosphate buffer (pH 5.52): acetonitrile (55:45), at a flow rate of 1.0 ml/min and 17-minute run time.…”

“…In addition, the clearance of ICG is used to evaluate hepatic function pre- and post-liver transplantation [10] and recent studies have found ICG to be a more reliable indicator of liver function post-operatively than other conventional endogenous markers such as bilirubin and prothrombin time [11]. Several studies performed in experimental models have examined the clearance of ICG as a functional marker of liver injury [6,12,13]. However, the clearance of ICG has not been previously studied as an endpoint to assess the effectiveness of treatments for drug-induced toxicity.…”

Aqueous Solubility, n-Octanol–Water Partition Coefficient, and Sorption of Five Selective Serotonin Reuptake Inhibitors to Sediments and Soils

“…Others are as follows: clay content, r = 0.03-0.38; organic matter content, r = 0.12-0.48; CEC, r = 0.13-0.27. Kinney et al (2006) have reported that although having high water solubility (12,900 mg/L) (Chen et al 2002), high pK a (9.4-9.5) (Dasmalchi et al 1995;Kulkarni and Pegram 2000), and low log K ow (Snyder et al 2003), acetaminophen accumulated in soil as much as other pharmaceuticals (erythromycin, carbamazepine, and fluoxetine) with low water solubility less than 100 mg L -1 and relatively high log K ow did. Like acetaminophen, all the SSRIs had high water solubility (3,022-15,460 mg/L), high pK a (9.39-10.32) (Vasskog et al 2006), and low log K ow (1.12-1.39).…”

Clinical trials in cystic fibrosis

“…Another difference of murine CF models as compared to humans concerns drug clearance [123]. Mice are also available which over-express the sodium channel EnaC and show CF like lung disease [124].…”