Minimal contribution of the hepatic uptake transporter OATP1B1 to the inter-individual variability in SN-38 pharmacokinetics in cancer patients without severe renal failure.
PURPOSE
SN-38, a pharmacologically active metabolite of irinotecan, is taken up into hepatocytes by organic anion transporting polypeptide (OATP) 1B1. The effects of functional OATP1B1 521T>C on the pharmacokinetics of SN-38 remain controversial. Here, we prospectively examined the effects of OATP1B1 function on the area under the plasma total or unbound concentration-time curve (tAUC or uAUC) of SN-38 by assessing OATP1B1 521T>C and the plasma levels of endogenous OATP1B1 substrates, coproporphyrin (CP)-I and III, in cancer patients treated with irinotecan.


METHODS
We enrolled cancer patients who were treated with an irinotecan-containing regimen and did not have severe renal failure. The total and unbound concentrations of SN-38 in the plasma were measured by high-performance liquid chromatography. AUC values were calculated and normalized to the actual irinotecan dose (AUC/dose). The OATP1B1 521T>C was analyzed by direct sequencing. Concentrations of the endogenous substrates in plasma before irinotecan treatment (baseline) were determined by liquid chromatography with tandem mass spectrometry.


RESULTS
Twenty-two patients with a median estimated glomerular filtration rate of 74.8 mL/min (range 32.6-99.6) were examined. Both tAUC/dose and uAUC/dose were associated with the grade of neutropenia; however, they were not associated with OATP1B1 521T>C or baseline CP-I and III levels. It is worth noting that these baseline concentrations were significantly higher in patients with OATP1B1 521C, supporting functional changes in OATP1B1.


CONCLUSION
The contribution of OATP1B1 activity to inter-patient variability in the systemic exposure to SN-38 is likely minimal in patients without severe renal failure.
['Tsuboya|Ayako|A|', 'Kubota|Yutaro|Y|', 'Ishida|Hiroo|H|', 'Ohkuma|Ryotaro|R|', 'Ishiguro|Tomoyuki|T|', 'Hirasawa|Yuya|Y|', 'Ariizumi|Hirotsugu|H|', 'Tsunoda|Takuya|T|', 'Sasaki|Yasutsuna|Y|', 'Matsumoto|Natsumi|N|', 'Kondo|Yusuke|Y|', 'Tomoda|Yukana|Y|', 'Kusuhara|Hiroyuki|H|', 'Fujita|Ken-Ichi|KI|0000-0002-1575-6690']
D000368:Aged D019540:Area Under Curve D002853:Chromatography, Liquid D004305:Dose-Response Relationship, Drug D005260:Female D005919:Glomerular Filtration Rate D006801:Humans D000077146:Irinotecan D027381:Liver-Specific Organic Anion Transporter 1 D008297:Male D008875:Middle Aged D009369:Neoplasms D011446:Prospective Studies D051437:Renal Insufficiency D012720:Severity of Illness Index D053719:Tandem Mass Spectrometry D059004:Topoisomerase I Inhibitors
OATP1B1 SN-38 Pharmacokinetics Irinotecan Coproporphyrin-I