Histopathology and biochemistry analysis of the interaction between sunitinib and paracetamol in mice.

BACKGROUND: Sunitinib, a tyrosine kinase inhibitor to treat GIST and mRCC may interact with paracetamol as both undergo P450 mediated biotransformation and P-glycoprotein transport. This study evaluates the effects of sunitinib-paracetamol coadministration on liver and renal function biomarkers and liver, kidney, brain, heart and spleen histopathology. ICR male mice (n = 6 per group/dose) were administered saline (group-A) or paracetamol 500 mg/kg IP (group-B), or sunitinib at 25, 50, 80, 100, 140 mg/kg PO (group-C) or coadministered sunitinib at 25, 50, 80, 100, 140 mg/kg PO and paracetamol IP at fixed dose 500 mg/kg (group-D). Paracetamol was administered 15 min before sunitinib. Mice were sacrificed 4 h post sunitinib administration. RESULTS: Group-A serum ALT and AST levels were 14.29 ± 2.31 U/L and 160.37 ± 24.74 U/L respectively and increased to 249.6 ± 222.7 U/L and 377.1 ± 173.6 U/L respectively in group-B; group-C ALT and AST ranged 36.75-75.02 U/L and 204.4-290.3 U/L respectively. After paracetamol coadministration with low sunitinib doses (group-D), ALT and AST concentrations ranged 182.79-221.03 U/L and 259.7-264.4 U/L respectively, lower than group-B. Paracetamol coadministration with high sunitinib doses showed higher ALT and AST values (range 269.6-349.2 U/L and 430.2-540.3 U/L respectively), p < 0.05. Hepatic histopathology showed vascular congestion in group-B; mild congestion in group-C (but lesser than in group-B and D). In group-D, at low doses of sunitinib, lesser damage than in group-B occurred but larger changes including congestion were observed at high sunitinib doses. BUN levels were higher (p < 0.05) for group-B (33.81 ± 5.68 mg/dL) and group-D (range 35.01 ± 6.95 U/L to 52.85 ± 12.53 U/L) compared to group-A (15.60 ± 2.17 mg/dL) and group-C (range 17.50 ± 1.25 U/L to 26.68 ± 6.05 U/L). Creatinine remained unchanged. Renal congestion and necrosis was lower in group-C than group-B but was higher in group-D (p > 0.05). Mild cardiotoxicity occurred in groups B, C and D. Brain vascular congestion occurred at high doses of sunitinib administered alone or with paracetamol. Hepatic and renal biomarkers correlated with histopathology signs. CONCLUSIONS: Paracetamol and sunitinib coadministration may lead to dose dependent outcomes exhibiting mild hepatoprotective effect or increased hepatotoxicity. Sunitinib at high doses show renal, cardiac and brain toxicity. Liver and renal function monitoring is recommended.

Maternal plasma soluble fms-like tyrosine kinase-1 and placental growth factor levels as biochemical markers of gestational hypertension for Malaysian mothers.

AIMS: To establish baseline levels of maternal plasma soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) among normotensive Malaysian mothers and to compare the marker levels between normotensives and mothers with gestational hypertension (GH). METHODS: Plasma sFlt-1 and PlGF were measured by enzyme-linked immunosorbent assay in an unmatched, case-control study. The results were subjected to normality testing and analyzed by Mann-Whitney U-tests. RESULTS: Among normotensive mothers, both sFlt-1and PlGF showed a general increase in levels from the 24th to 32nd weeks of pregnancy. PlGF levels in normotensive mothers with gestational diabetes mellitus were reduced compared to those without the disease, while levels of sFlt-1 were elevated. Mothers with GH had reduced levels of PlGF with increased levels of sFlt-1 when compared to normotensive mothers. Among the normotensive mothers followed up until delivery, the inversed pattern of reduced PlGF and increased sFlt-1 marker levels was found in 40% of those who developed GH later in pregnancy. CONCLUSIONS: Plasma levels of sFlt-1and PlGF in normotensive mothers may be influenced by gestational diabetes mellitus and GH. GH mothers show an inversed pattern of marker levels compared to normotensive mothers.