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<p>Cynomolgus monkeys are widely utilized for understanding and predicting human pharmacokinetics (PK) of OATP1B substrates due to their close evolutionary relationship with humans and the high degree of transporter protein homology similarities. We note that some OATP1B tool substrates (e.g., cerivastatin and repaglinide) have steady state volume of distribution (V<sub>SS</sub>) values in monkeys that are larger than corresponding V<sub>SS</sub> values reported for humans. To understand V<sub>SS</sub> and tissue biodistribution of substrate drugs in monkeys, we have performed a series of monkey PK and tissue distribution studies, as well as data analysis with physiologically based pharmacokinetic (PBPK) modeling for several OATP1B substrates (i.e., cerivastatin, repaglinide, glyburide, rosuvastatin, and valsartan). We find that there are unexpectedly high accumulations of these compounds in monkey intestines potentially involving transporter mediated active uptake, which contributed to the higher-than-expected V<sub>SS</sub> values.</p> Graphical Abstract <p></p>

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Biodistribution of Cerivastatin, Repaglinide, Glyburide, Rosuvastatin, and Valsartan in Cynomolgus Monkeys and PBPK Analysis

  • 期刊论文

  • 发表日期：

    2026年4月8日

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  • Rui Li,
  • Samantha Jordan,
  • Mark Niosi,
  • Manthena V. S. Varma,
  • Li Di

摘要

Cynomolgus monkeys are widely utilized for understanding and predicting human pharmacokinetics (PK) of OATP1B substrates due to their close evolutionary relationship with humans and the high degree of transporter protein homology similarities. We note that some OATP1B tool substrates (e.g., cerivastatin and repaglinide) have steady state volume of distribution (VSS) values in monkeys that are larger than corresponding VSS values reported for humans. To understand VSS and tissue biodistribution of substrate drugs in monkeys, we have performed a series of monkey PK and tissue distribution studies, as well as data analysis with physiologically based pharmacokinetic (PBPK) modeling for several OATP1B substrates (i.e., cerivastatin, repaglinide, glyburide, rosuvastatin, and valsartan). We find that there are unexpectedly high accumulations of these compounds in monkey intestines potentially involving transporter mediated active uptake, which contributed to the higher-than-expected VSS values.

Graphical Abstract