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Pharmacokinetics and Urinary Excretion Mechanism of Orteronel (TAK-700), A Novel 17,20-Lyase Inhibitor, in Animals

A Goto1, Y Moriya1, T Takeuchi1

  • 1Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.

Drug Research
|September 30, 2015
PubMed

Insights

Orteronel, a prostate cancer drug, is mainly excreted unchanged in urine via kidney tubules in rats and monkeys. Non-saturable uptake significantly contributes to its renal excretion, with some carrier-mediated transport involved.

Area of Science:

  • Pharmacology
  • Nephrology
  • Oncology

Background:

  • Orteronel is a selective 17,20-lyase inhibitor investigated for castration-resistant prostate cancer.
  • Understanding the absorption, distribution, metabolism, and excretion (ADME) of orteronel is crucial for its clinical development.

Purpose of the Study:

  • To investigate the absorption and disposition of [(14)C]orteronel in rats and monkeys.
  • To elucidate the mechanisms of renal excretion, particularly the role of tubular secretion and carrier-mediated transport.

Main Methods:

  • Oral administration of [(14)C]orteronel to rats and monkeys.
  • Analysis of urinary excretion and unbound-based renal clearances.
  • In vitro uptake studies using rat kidney slices to assess carrier-mediated transport.

Main Results:

  • Orteronel was extensively excreted unchanged in the urine of both species.
  • Renal clearances exceeded glomerular filtration rates, indicating significant tubular secretion.
  • Rat kidney slice studies suggested digoxin-sensitive (Oatp4c1) and non-saturable transport mechanisms for renal uptake.

Conclusions:

  • Urinary tubular secretion plays a key role in the renal excretion of orteronel.
  • Non-saturable uptake is the primary contributor to renal excretion in rats, with a minor role for saturable, carrier-mediated transport.

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