ABC Transporter Functions as Determined from Combination Knockout Mice
Findings | ||||
---|---|---|---|---|
Combination Knockout | Substrate | Transporter | Function | References |
Abcb1a −/− /Abcb1b −/− /Abcc1 −/− | Etoposide | P-gp | restricts brain penetration | (5, 6) |
Abcc1 | limits accumulation in the cerebrospinal fluid | |||
P-gp and Abcc1 | protect against etoposide-induced toxicity | |||
Abcb1a −/− /Abcb1b −/− /Abcg2 −/− | Topotecan | P-gp | mediates elimination and restricts brain penetration | (40) |
Abcg2 | limits oral uptake and mediates elimination | |||
Abcg2 | restricts brain penetration when P-gp is absent | |||
Imatinib | P-gp | mediates fecal excretion and restricts brain penetration | (42) | |
Abcg2 | has minor impact on fecal excretion; partially limits brain penetration when P-gp is absent | |||
Lapatinib | P-gp | restricts brain penetration | (43) | |
Abcg2 | partially restricts brain penetration when P-gp is absent | |||
Dasatinib | P-gp | limits oral availability and restricts brain penetration | (44) | |
Abcg2 | partially restricts brain penetration when P-gp is absent | |||
Abcb1a −/− /Abcb1b −/− /Abcc2 −/− | Doxorubicin | P-gp | main transporter for biliary excretion | (52) |
Abcc2 | partly compensates for the absence of P-gp | |||
Paclitaxel | P-gp | limits oral uptake and facilitates direct intestinal excretion | (8) | |
Abcc2 | is main transporter for biliary excretion; influences oral pharmacokinetics when P-gp is absent | |||
P-gp and Abcc2 | equally affect iv pharmacokinetics | |||
Abcc2−/−/Abcc3−/− and Abcc2−/−/Abcg2−/− | Methotrexate | Abcc2 | is the main transporter for biliary excretion | (12, 61) |
Abcg2 | mediates biliary and urinary excretion when Abcc2 is absent | |||
Abcc3 | mediates sinusoidal excretion from the liver when Abcc2 is absent | |||
7-Hydroxy-methotrexate | Abcc2 | is the main transporter for biliary excretion | ||
Abcg2 | mediates biliary and urinary excretion when Abcc2 is absent | |||
Abcc3 | mediates sinusoidal excretion from the liver when Abcc2 is absent | |||
Abcc2 −/− /Abcc3 −/− | Morphine-3- glucuronide | Abcc2 | is the main transporter for biliary excretion | (11) |
Abcc3 | mediates sinusoidal excretion from the liver when Abcc2 is absent | |||
Fexofenadine | Abcc2 | mediates biliary excretion | (13) | |
Abcc3 | mediates sinusoidal excretion from the liver |