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Related Experiment Videos

Single-point plasma or urine dextromethorphan method for determining CYP3A activity.

Benjamin Pei-Chung Kuo1, Oliver Yoa-Pu Hu, Cheng-Huei Hsiong

  • 1Graduate Institute of Life Sciences, National Defense Medical Center and Academy Sinica, Taipei, Taiwan, ROC.

Biopharmaceutics & Drug Disposition
|December 23, 2003
PubMed
Summary

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This study validates using the metabolic ratio of dextromethorphan to 3-methoxymorphinan as a reliable probe for assessing cytochrome P450 3A (CYP3A) activity in vivo. Various sample types and time points proved effective for phenotyping CYP3A.

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Biochemical Assays

Background:

  • Dextromethorphan is a common substrate for phenotyping cytochrome P450 2D6 (CYP2D6).
  • Cytochrome P450 3A4/5 (CYP3A4/5) also metabolizes dextromethorphan to 3-methoxymorphinan.
  • The metabolic ratio (MR) of dextromethorphan/3-methoxymorphinan is explored as a potential in vivo probe for CYP3A activity.

Purpose of the Study:

  • To evaluate the repeatability and validity of using the dextromethorphan/3-methoxymorphinan metabolic ratio (MR) for phenotyping CYP3A activity.
  • To assess various sample types (plasma, saliva, urine) and time points for determining the MR.
  • To compare MRs obtained from single and multiple dosing regimens.

Main Methods:

  • Subjects received single (15 mg immediate-release) or multiple (60 mg controlled-release twice daily for 5 days) doses of dextromethorphan.

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  • Plasma, saliva, and urine samples were collected at various time points.
  • Dextromethorphan and 3-methoxymorphinan concentrations were measured using high-performance liquid chromatography (HPLC).

    • Main Results:

    • Both single and multiple dosing studies showed good repeatability of the MR across different periods.
    • Urine MRs from 0-6, 0-8, and 0-12 hour intervals correlated significantly with 0-24 hour MRs in the single-dose study.
    • Plasma MRs (0.5-12 h), saliva MRs (at 12 h), and various urine MR intervals (0-24 h) in the multiple-dose study predicted the overall MR (AUCtau(ss)).

    Conclusions:

    • The dextromethorphan/3-methoxymorphinan MR is a repeatable and valid method for in vivo CYP3A phenotyping.
    • Specific urine collection intervals (0-6, 0-8, 0-12 h) after single or multiple doses are suitable.
    • Saliva (12 h) and plasma (0.5-12 h) samples also provide reliable data for assessing CYP3A activity.