Inhibition of mycophenolic acid glucuronidation by niflumic acid in human liver microsomes

M. Vietri, A. Pietrabissa, F. Mosca, G. M. Pacifici

Research output: Contribution to journalArticle

Abstract

Objectives: The first aim of this investigation was to study the variability of mycophenolic acid (MPA) glucuronidation rate in human liver. The second aim was to study the inhibition type of niflumic acid (NA) for MPA glucuronidation in human liver. The third aim was to study the variability of the IC50 value of NA for MPA glucuronidation in human liver. Methods: The rate of MPA glucuronidation was measured by employing an assay based on uridine 5′-di- phosphate-[U-14C]-glucuronic acid (UDPGA), and MPA glucuronide was isolated by means of thin-layer chromatography. The necessary concentration for UDPGA and MPA was 1 mM. The rate of MPA glucuronidation was measured in 50 human liver samples. The inhibition type of NA for MPA glucuronidation was studied in 5 human liver samples. The NA IC50 value was measured in 27 human liver samples using six concentrations of NA ranging from 1.05 μM to 34 μM. Results: MPA glucuronidation rate was positively skewed, was not gender regulated and did not correlate with the liver donor's age. The rate of MPA glucuronidation varied 4.8-fold within the 5th and 95th percentiles, with a mean±SD and a median of 2.8±1.0 nmol/min/mg and 2.5 nmol/min/mg, respectively. The inhibition type of NA for MPA glucuronidation was mixed non-competitive. The Ki value of NA (mean±SD) was 15±10 lM and, in non-inhibited samples, the Km value for MPA was 0.41±0.06 mM. The distribution of NA IC50 value varied 3.3-fold within the 5th and 95th percentiles with a mean±SD and a median of 5.6±2.1 lM and 5.2 lM, respectively. The distribution of NA IC50 value did not deviate significantly from normality. Conclusion: The range of hepatic rate of MPA glucuronidation is narrow relative to those of ethinyloestradiol, testosterone and zidovudine glucuronidation obtained from literature. The Ki value of NA is one order of magnitude lower than the Km for MPA in non-inhibited samples. This indicates that the inhibitor affinity for glucuronosyl transferase is greater than that of the substrate. The range of variation of NA IC50 values is narrow.

Original languageEnglish
Pages (from-to)93-97
Number of pages5
JournalCancer Chemotherapy and Pharmacology, Supplement
Volume49
Issue number7
Publication statusPublished - 2002

Fingerprint

Niflumic Acid
Mycophenolic Acid
Liver Microsomes
Inhibitory Concentration 50
Liver
Uridine Diphosphate Glucuronic Acid
Glucuronic Acid
Ethinyl Estradiol
Zidovudine
Uridine
Thin Layer Chromatography
Transferases

Keywords

  • Glucuronosyl transferase
  • Liver
  • Mycophenolic acid
  • Niflumic acid
  • Variability

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology

Cite this

Inhibition of mycophenolic acid glucuronidation by niflumic acid in human liver microsomes. / Vietri, M.; Pietrabissa, A.; Mosca, F.; Pacifici, G. M.

In: Cancer Chemotherapy and Pharmacology, Supplement, Vol. 49, No. 7, 2002, p. 93-97.

Research output: Contribution to journalArticle

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title = "Inhibition of mycophenolic acid glucuronidation by niflumic acid in human liver microsomes",
abstract = "Objectives: The first aim of this investigation was to study the variability of mycophenolic acid (MPA) glucuronidation rate in human liver. The second aim was to study the inhibition type of niflumic acid (NA) for MPA glucuronidation in human liver. The third aim was to study the variability of the IC50 value of NA for MPA glucuronidation in human liver. Methods: The rate of MPA glucuronidation was measured by employing an assay based on uridine 5′-di- phosphate-[U-14C]-glucuronic acid (UDPGA), and MPA glucuronide was isolated by means of thin-layer chromatography. The necessary concentration for UDPGA and MPA was 1 mM. The rate of MPA glucuronidation was measured in 50 human liver samples. The inhibition type of NA for MPA glucuronidation was studied in 5 human liver samples. The NA IC50 value was measured in 27 human liver samples using six concentrations of NA ranging from 1.05 μM to 34 μM. Results: MPA glucuronidation rate was positively skewed, was not gender regulated and did not correlate with the liver donor's age. The rate of MPA glucuronidation varied 4.8-fold within the 5th and 95th percentiles, with a mean±SD and a median of 2.8±1.0 nmol/min/mg and 2.5 nmol/min/mg, respectively. The inhibition type of NA for MPA glucuronidation was mixed non-competitive. The Ki value of NA (mean±SD) was 15±10 lM and, in non-inhibited samples, the Km value for MPA was 0.41±0.06 mM. The distribution of NA IC50 value varied 3.3-fold within the 5th and 95th percentiles with a mean±SD and a median of 5.6±2.1 lM and 5.2 lM, respectively. The distribution of NA IC50 value did not deviate significantly from normality. Conclusion: The range of hepatic rate of MPA glucuronidation is narrow relative to those of ethinyloestradiol, testosterone and zidovudine glucuronidation obtained from literature. The Ki value of NA is one order of magnitude lower than the Km for MPA in non-inhibited samples. This indicates that the inhibitor affinity for glucuronosyl transferase is greater than that of the substrate. The range of variation of NA IC50 values is narrow.",
keywords = "Glucuronosyl transferase, Liver, Mycophenolic acid, Niflumic acid, Variability",
author = "M. Vietri and A. Pietrabissa and F. Mosca and Pacifici, {G. M.}",
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T1 - Inhibition of mycophenolic acid glucuronidation by niflumic acid in human liver microsomes

AU - Vietri, M.

AU - Pietrabissa, A.

AU - Mosca, F.

AU - Pacifici, G. M.

PY - 2002

Y1 - 2002

N2 - Objectives: The first aim of this investigation was to study the variability of mycophenolic acid (MPA) glucuronidation rate in human liver. The second aim was to study the inhibition type of niflumic acid (NA) for MPA glucuronidation in human liver. The third aim was to study the variability of the IC50 value of NA for MPA glucuronidation in human liver. Methods: The rate of MPA glucuronidation was measured by employing an assay based on uridine 5′-di- phosphate-[U-14C]-glucuronic acid (UDPGA), and MPA glucuronide was isolated by means of thin-layer chromatography. The necessary concentration for UDPGA and MPA was 1 mM. The rate of MPA glucuronidation was measured in 50 human liver samples. The inhibition type of NA for MPA glucuronidation was studied in 5 human liver samples. The NA IC50 value was measured in 27 human liver samples using six concentrations of NA ranging from 1.05 μM to 34 μM. Results: MPA glucuronidation rate was positively skewed, was not gender regulated and did not correlate with the liver donor's age. The rate of MPA glucuronidation varied 4.8-fold within the 5th and 95th percentiles, with a mean±SD and a median of 2.8±1.0 nmol/min/mg and 2.5 nmol/min/mg, respectively. The inhibition type of NA for MPA glucuronidation was mixed non-competitive. The Ki value of NA (mean±SD) was 15±10 lM and, in non-inhibited samples, the Km value for MPA was 0.41±0.06 mM. The distribution of NA IC50 value varied 3.3-fold within the 5th and 95th percentiles with a mean±SD and a median of 5.6±2.1 lM and 5.2 lM, respectively. The distribution of NA IC50 value did not deviate significantly from normality. Conclusion: The range of hepatic rate of MPA glucuronidation is narrow relative to those of ethinyloestradiol, testosterone and zidovudine glucuronidation obtained from literature. The Ki value of NA is one order of magnitude lower than the Km for MPA in non-inhibited samples. This indicates that the inhibitor affinity for glucuronosyl transferase is greater than that of the substrate. The range of variation of NA IC50 values is narrow.

AB - Objectives: The first aim of this investigation was to study the variability of mycophenolic acid (MPA) glucuronidation rate in human liver. The second aim was to study the inhibition type of niflumic acid (NA) for MPA glucuronidation in human liver. The third aim was to study the variability of the IC50 value of NA for MPA glucuronidation in human liver. Methods: The rate of MPA glucuronidation was measured by employing an assay based on uridine 5′-di- phosphate-[U-14C]-glucuronic acid (UDPGA), and MPA glucuronide was isolated by means of thin-layer chromatography. The necessary concentration for UDPGA and MPA was 1 mM. The rate of MPA glucuronidation was measured in 50 human liver samples. The inhibition type of NA for MPA glucuronidation was studied in 5 human liver samples. The NA IC50 value was measured in 27 human liver samples using six concentrations of NA ranging from 1.05 μM to 34 μM. Results: MPA glucuronidation rate was positively skewed, was not gender regulated and did not correlate with the liver donor's age. The rate of MPA glucuronidation varied 4.8-fold within the 5th and 95th percentiles, with a mean±SD and a median of 2.8±1.0 nmol/min/mg and 2.5 nmol/min/mg, respectively. The inhibition type of NA for MPA glucuronidation was mixed non-competitive. The Ki value of NA (mean±SD) was 15±10 lM and, in non-inhibited samples, the Km value for MPA was 0.41±0.06 mM. The distribution of NA IC50 value varied 3.3-fold within the 5th and 95th percentiles with a mean±SD and a median of 5.6±2.1 lM and 5.2 lM, respectively. The distribution of NA IC50 value did not deviate significantly from normality. Conclusion: The range of hepatic rate of MPA glucuronidation is narrow relative to those of ethinyloestradiol, testosterone and zidovudine glucuronidation obtained from literature. The Ki value of NA is one order of magnitude lower than the Km for MPA in non-inhibited samples. This indicates that the inhibitor affinity for glucuronosyl transferase is greater than that of the substrate. The range of variation of NA IC50 values is narrow.

KW - Glucuronosyl transferase

KW - Liver

KW - Mycophenolic acid

KW - Niflumic acid

KW - Variability

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