Analysis Tools
homeostasis/metabolism
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• adult mice develop normally and show no significant changes in markers of liver function (e.g. alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase or total bilirubin) or other markers of renal function (e.g. calcium, creatinine or creatine kinase) relative to wild-type controls
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• adult mice show a modest but significant increase in blood urea nitrogen level relative to wild-type controls
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• after oral administration, the area under the curve (AUC) of fluvastatin (a known SLCO2B1 substrate drug) is decreased by ~2-fold in males and by ~3-fold in females; however, no differences in liver concentrations of fluvastatin are observed 4 h after oral administration, regardless of sex
• after intravenous administration, measures of systemic exposure to fluvastatin are slightly reduced in males, but not in females; however, no differences are found in the clearance of fluvastatin after tail vein injection, regardless of sex
• absolute oral bioavailability of fluvastatin is decreased in both females (12.8% versus 31.5% in wild-type females) and males (20.5% versus 29.6% in wild-type males)
• pretreatment with oral erlotinib (a tyrosine kinase inhibitor that targets EGFR, and novel potent inhibitor of SLCO2B1) fails to decrease the AUC of fluvastatin, unlike in erlotinib-treated wild-type controls; however, no differences in fluvastatin liver exposure or liver to plasma ratio are found between vehicle- or erlotinib-treated mice and their corresponding wild-type controls
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