Table 4.

Summary of metabolic changes upon dosing with compounds A and B.

Drug	Blood	Urine	Histopathology	Liver toxicogenomics
Compound A	Creatinine ↓ (L, H) Phospholipids ↓ (L, H) ALP, total protein, globulin. ↓ (H) Albumin ↓ ( H) Albumin/globulin ↓ (L, H) ASAT, ALAT ↑(H) Tyrosine ↓ (H)*	Biochemistry pH ↓ (L, H) Creatinine ↓ (H) Phospholipids ↓ (L, H) Ca++, K+ ↓ (L, H) Inorganic PO4 ↑ (L, H) NMR analysis PAG ↑ (2× L, 2-4x H) Citrate, 2OG, fumarate, malate, isocitrate, succinate ↓ (H) Taurine ↓ (H) Carnitine, creatine ↑ (H) Proteomics Clear sign of nephrotoxicity (H)*	Vacuolated foamy macrophages lungs, mesenteric lymph nodes (L, H), spleen (H) Vacuolated hepatocytes (L,H). Associated toxicity (necrosis) in liver, kidney, spleen, mesenteric lymph nodes (predominantly H).	Call of hepatotoxicity, steatosis/cholestasis. Partly reversible at 168 h PAH ↓ FA-metabolism ↑ FA synthase ↓ Stearoyl CoA desaturase ↓ ATP citrate lyase ↓ Fumarate hydratase ↑ General stress response
Compound B	Total protein ↓ (H)	NMR analysis No significant drug-induced changes	Single cell liver necrosis (L, H, 48 h, postdose)	Individual animals with borderline cholestasis-like evidence (L, H) Slight PAH ↓ Slight FA synthase ↓ Slight ATP citrate lyase ↓ Slight fumarate hydratase ↑

^*Tested only with high doses.

2OG, 2-oxoglutarate; ALAT, alanine aminotransferase; ALP, alkaline phosphatase; ATP, adenosine triphosphate; ASAT, aminotransferase; FA, fatty acid; H, high dose; L, low dose; PAG, phenylacetylglycine; PAH, phenylalanine hydroxylase.