Mechanism of hepatic uptake transport and bile excretion in hepatobiliary scintigraphy with a ^99mTc labeled pyridoxylaminate group

Objectives In the hepatobiliary scintigraphy, ^99mTc-N-pyridoxyl-5-methyltryptophan (^99mTc-PMT) is one of ^99mTc-pyridoxylaminates group and best radiopharmaceutical, which is used in Japan. However, the mechanism of hepatic uptake transport and excretion in the bile has not been revealed in all radiopharmaceuticals in the hepatobiliary scintigraphy. We investigated the mechanism on the ^99mTc-PMT.

Methods Five of solute carrier (SLC) transporters on the hepatic uptake were evaluated using normal rat’s hepatic primary culture cells and human embryonic kidney (HEK) cells with high expression of each SLC transporter. These cells were incubated by the ^99mTc-PMT and measured by a gamma counter. On the other hand, adenosine triphosphate-binding cassette (ABC) transporters on the bile excretion were examined using main hepatic ABC transporter vesicles expressed multiple drug resistance 1 (MDR1), multidrug resistance-associated protein 2 (MRP2), breast cancer resistance protein or bile salt export pump. ^99mTc-PMT was incubated for 1, 3 and 5 min with adenosine triphosphate or adenosine monophosphate and these vesicles were measured by a gamma counter.

Results In the SLC transporters, we confirmed involvement of organic anion transporting polypeptide (OATP) 1B1 and Na⁺-taurocholate cotransporting polypeptide (NTCP). In the ABC transporters, MDR1 and MRP2 were identified as the mechanism of bile excretion.

Conclusions ^99mTc-PMT is extracted into hepatocytes from OATP1B1 and NTCP and excreted into bile canalculi via the MDR1 and MRP2. The mechanism of ^99mTc-iminodiacetic acid analogues (^99mTc-disofenin or mebrofenin, etc) also should be revealed as well as ^99mTc-PMT because the mechanism may be different from ^99mTc-PMT