A monkey model of acetaminophen-induced hepatotoxicity; phenotypic similarity to human.

Species-specific differences in the hepatotoxicity of acetaminophen (APAP) have been shown. To establish a monkey model of APAP-induced hepatotoxicity, which has not been previously reported, APAP at doses up to 2,000 mg/kg was administered orally to fasting male and female cynomolgus monkeys (n = 3-5/group) pretreated intravenously with or without 300 mg/kg of the glutathione biosynthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO). In all the animals, APAP at 2,000 mg/kg with BSO but not without BSO induced hepatotoxicity, which was characterized histopathologically by centrilobular necrosis and vacuolation of hepatocytes. Plasma levels of APAP and its reactive metabolite N-acethyl-p-benzoquinone imine (NAPQI) increased 4 to 7 hr after the APAP treatment. The mean Cmax level of APAP at 2,000 mg/kg with BSO was approximately 200 µg/mL, which was comparable to high-risk cutoff value of the Rumack-Matthew nomogram. Interestingly, plasma alanine aminotransferase (ALT) did not change until 7 hr and increased 24 hr or later after the APAP treatment, indicating that this phenotypic outcome was similar to that in humans. In addition, circulating liver-specific miR-122 and miR-192 levels also increased 24 hr or later compared with ALT, suggesting that circulating miR-122 and miR-192 may serve as potential biomarkers to detect hepatotoxicity in cynomolgus monkeys. These results suggest that the hepatotoxicity induced by APAP in the monkey model shown here was translatable to humans in terms of toxicokinetics and its toxic nature, and this model would be useful to investigate mechanisms of drug-induced liver injury and also potential translational biomarkers in humans.

Sildenafil-induced reversible impairment of rod and cone phototransduction in monkeys.

PURPOSE: To investigate functional alteration of the retina induced by sildenafil in monkeys. METHODS: Sildenafil was administered intravenously to cynomolgus monkeys at dose levels of 0, 1, 3, and 10 mg/kg, and standard full-field electroretinograms (ERGs) were recorded. The rod and cone a-waves in response to high-intensity flashes were also analyzed by the a-wave fitting model (a-wave analysis). Additionally, the photopic negative responses were recorded. RESULTS: Sildenafil at 3 mg/kg or more induced the following alterations in the standard full-field ERGs immediately after dosing: delayed b-wave in the rod response; delayed a-wave in the combined rod-cone response; and attenuated b-waves in the single-flash cone response and in the 30 Hz flicker. Additionally, the following changes were observed in the 10 mg/kg group: attenuated b-wave in the rod response; attenuated a-wave and delayed b-wave in the combined rod-cone response; delayed oscillatory potentials; and attenuated and delayed a-wave in the single-flash cone response. In the a-wave analysis immediately after dosing, sildenafil selectively decreased the sensitivity parameter (S) in the cone a-wave at 3 mg/kg, and in both the rod and cone a-waves at 10 mg/kg. The S value was highly correlated with plasma sildenafil concentration. The above changes fully recovered 24 hours after dosing. CONCLUSIONS: Sildenafil produced reversible impairment of the rod and cone phototransduction in monkeys. Meanwhile, involvement of the postreceptoral retinal components was suggested. These findings contribute to the clarification of sildenafil-induced visual disturbances. It is suggested that the photoreceptors are predominantly, but not exclusively, affected in the retina of humans with sildenafil-induced visual disturbances.

Decrease in protein binding and its effect on toxicokinetics (TK)/toxicodynamics (TD) of diclofenac and propranolol in pregnant rats.

Plasma protein binding is an important factor for the kinetics of drugs and how they act since it is the first step in drug distribution. Physiological changes in pregnancy, which include plasma composition, can affect drug binding and subsequent drug response. In the present study, we investigated the toxicokinetics (TK) and/or toxicodynamics (TD) of diclofenac and propranolol comparing pregnant Sparague-Dawley (SD) rats with non-pregnant SD rats in terms of protein binding and drug distribution. Diclofenac and propranolol are reported to bind to albumin and alpha(1)-acid glycoprotein (AGP), respectively. After a single administration of diclofenac, the area under plasma concentration-time curve (AUC) based on free diclofenac in pregnant rats was 3.9 times higher than that in non-pregnant rats. This difference is considered to be due to a lower concentration of serum albumin and a higher concentration of non-esterified fatty acid (NEFA) that inhibits drug binding to albumin, in pregnant rats. In histopathological examination, more severe gastrointestinal toxicity was observed in pregnant rats at 24 hr after dosing. This severe toxicity was likely to be correlated with the higher AUC. With respect to propranolol, the difference of the AUC based on free propranolol was not clear although the concentration of serum AGP was lower in pregnant rats. However, the binding analysis data suggested a difference of protein binding at a lower propranolol concentration range. Consequently, lowered serum proteins and increased NEFA in pregnant rats can lead to low protein binding, subsequent increase in free drug concentrations, and eventual increase in the TD of drugs.