Homozygously mdr1a gene disrupted mice (mdr1a(−/−) mice) and wild type mice (mdr1a(+/+) mice) were used to develop a method for P‐glycoprotein (P‐gp) function imaging non‐invasively and to study the effect of a P‐gp reversal agent on its function in vivo.

[¹¹C]verapamil (0.1 mg/kg) was administered and the changes in tissue concentrations were determined ex vivo by organ extirpation and in vivo with PET. To block P‐gp function, cyclosporin A was administered.

Biodistribution studies revealed 9.5‐fold (P<0.001) and 3.4‐fold (P<0.001) higher [¹¹C]verapamil in the brain and testes of mdr1a(−/−) mice than in mdr1a(+/+) mice. Cyclosporin A (25 mg/kg) increased [¹¹C]verapamil levels in the brain and testes of mdr1a(+/+) mice in both cases 3.3‐fold (P<0.01 (brain); P<0.001 (testes)). Fifty mg/kg cyclosporin A increased [¹¹C]verapamil in the brain 10.6‐fold (P<0.01) and in the testes 4.1‐fold (P<0.001). No increases were found in the mdr1a(−/−) mice. This indicates complete inhibition of P‐gp mediated [¹¹C]verapamil efflux.

Positron camera data showed lower [¹¹C]verapamil levels in the brain of mdr1a(+/+) mice compared to those in mdr1a(−/−) mice. [¹¹C]verapamil accumulation in the brain of mdr1a(+/+) mice was increased by cyclosporin A to levels comparable with those in mdr1a(−/−) mice, indicating that reversal of P‐gp mediated efflux can be monitored by PET.

We conclude that cyclosporin A can fully block the P‐gp function in the blood brain barrier and the testes and that PET enables the in vivo measurement of P‐gp function and reversal of its function non‐invasively.