Potential impact of underlying diseases influencing ADME in nonclinical safety assessment.

Nonclinical studies involve in vitro, in silico, and in vivo experiments to assess the toxicokinetics, toxicology, and safety pharmacology of drugs according to regulatory requirements by a national or international authority. In this review, we summarize the potential effects of various underlying diseases governing the absorption, distribution, metabolism, and excretion (ADME) of drugs to consider the use of animal models of diseases in nonclinical trials. Obesity models showed alterations in hepatic metabolizing enzymes, transporters, and renal pathophysiology, which increase the risk of drug-induced toxicity. Diabetes models displayed changes in hepatic metabolizing enzymes, transporters, and glomerular filtration rates (GFR), leading to variability in drug responses and susceptibility to toxicity. Animal models of advanced age exhibited impairment of drug metabolism and kidney function, thereby reducing the drug-metabolizing capacity and clearance. Along with changes in hepatic metabolic enzymes, animal models of metabolic syndrome-related hypertension showed renal dysfunction, resulting in a reduced GFR and urinary excretion of drugs. Taken together, underlying diseases can induce dysfunction of organs involved in the ADME of drugs, ultimately affecting toxicity. Therefore, the use of animal models of representative underlying diseases in nonclinical toxicity studies can be considered to improve the predictability of drug side effects before clinical trials.

[Outbreak of hepatitis by Orientia tsutsugamushi in the early years of the new millenium].

BACKGROUND/AIMS: Orientia -tsutsugamushi infection is an acute febrile disease due to the accidental transmission through human skin of forest dwelling vector Leptotrombidium larva. The authors observed liver dysfunctions in patients diagnosed with tsutsugamushi disease (Scrub typhus) in the past 3 years and report the data in the hope of bringing attention to this disease in the differential diagnosis of autumn-season hepatitis, especially of non-A, non-B and non-C hepatitis. METHODS: Medical records of 22 patients diagnosed with tsutsugamushi disease by the hemagglutinin method between October 2000 and November 2002 were reviewed. RESULTS: Female gender was dominant in the ratio of 3.4:1. Mean age was 56.4 +/- 2.6. Admission was between 23rd September and 15th November with the peak between mid October and early November. Fever, being the most common symptom, was observed in 21 cases, myalgia in 13, arthralgia in 12, chills in 6, and skin rash in 6. An incubation period of 7-9 days was most common (10 cases), 13-15 days (4), 10-12 days (3), within 3 days (3), and 4-6 days (2). Average ALT, AST and GGTP were increased to 93.2 +/- 17.3 IU/L (18 +/- 345 IU/L), 92.5 +/- 11.7 IU/L (34-255 IU/L) and 132.2 +/- 14.5 IU/L (19-251 IU/L), respectively, but total bilirubin was normal. All the patients improved with doxycycline therapy. CONCLUSIONS: Since it usually shows liver dysfunction, it is important to take Orientia tsutsugamushi into consideration in differential diagnosis of autumn-season, febrile hepatic disease.