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Pharmacokinetic Assessment of Multiple ATP-binding Cassette Transporters: The Power of Combination Knockout Mice
Table 1.
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 | |||
