CYP2C9 genotype and ibuprofen (IBU) pharmacokinetics (PK) in cystic fibrosis (CF)

D. J. Murry, G. L. Kearns, C. Oermann, A. Gaedigk, M. Sockrider, D. K. Seilheimer, J. S. Leeder

Research output: Contribution to journalArticle

Abstract

The PK of IBU (a CYP2C9 substrate) in patients with CF are extremely variable and can be unpredictable. IBU disposition was characterized in 26 patients with CF (5.5 to 29.6 years of age, 16.8-74.6 kg, BSA=0.73-1.93 m2) who received a single oral dose (20.7-27.9 mg/kg) of the drug. IBU was quantitated by HPLC and PK parameters determined by Bayesian estimation. CYP2C9 genotype was determined from leukocyte-derived genomic DNA using PCR RFLP. CYP2C9 genotype distribution was as follows: *1*1, n=14; *1*2, n=8; *1*3, n=2; *2*2, n=l and *2*3, n=1. IBU clearance (CL/F=ml/min/kg) (mean=1.49; range .71-2.59) was significantly correlated to body surface area (r2=0.39; p<.001), body weight (r2=0.36, p=.001), and age (r2=0.31; p=.003). CL/F in subjects with the *1*1 genotype (1.7±0.42) was significantly (p=0.02) greater than that observed in subjects with the *1*2 genotype ( 1.2±0.43). The mean subject age was not different between these subpopulations (e.g., *1*1 = 11.9 yr vs *1*2= 16.9 yr). Stepwise linear regression revealed that BSA (p<0.0001) or age (p=0.004) but not CYP2C9 genotype were significant determinants of IBU CL/F. Conclusion: Variability in the CL/F of IBU in CF is multifactorial and to a great degree is influenced by developmental differences in PK.

Original languageEnglish (US)
Number of pages1
JournalClinical Pharmacology and Therapeutics
Volume65
Issue number2
DOIs
StatePublished - Jan 1 1999

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Ibuprofen
Cystic Fibrosis
Pharmacokinetics
Genotype
Body Surface Area
Restriction Fragment Length Polymorphisms
Cytochrome P-450 CYP2C9
Linear Models
Leukocytes
High Pressure Liquid Chromatography
Body Weight
Polymerase Chain Reaction
DNA
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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CYP2C9 genotype and ibuprofen (IBU) pharmacokinetics (PK) in cystic fibrosis (CF). / Murry, D. J.; Kearns, G. L.; Oermann, C.; Gaedigk, A.; Sockrider, M.; Seilheimer, D. K.; Leeder, J. S.

In: Clinical Pharmacology and Therapeutics, Vol. 65, No. 2, 01.01.1999.

Research output: Contribution to journalArticle

Murry, D. J. ; Kearns, G. L. ; Oermann, C. ; Gaedigk, A. ; Sockrider, M. ; Seilheimer, D. K. ; Leeder, J. S. / CYP2C9 genotype and ibuprofen (IBU) pharmacokinetics (PK) in cystic fibrosis (CF). In: Clinical Pharmacology and Therapeutics. 1999 ; Vol. 65, No. 2.
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abstract = "The PK of IBU (a CYP2C9 substrate) in patients with CF are extremely variable and can be unpredictable. IBU disposition was characterized in 26 patients with CF (5.5 to 29.6 years of age, 16.8-74.6 kg, BSA=0.73-1.93 m2) who received a single oral dose (20.7-27.9 mg/kg) of the drug. IBU was quantitated by HPLC and PK parameters determined by Bayesian estimation. CYP2C9 genotype was determined from leukocyte-derived genomic DNA using PCR RFLP. CYP2C9 genotype distribution was as follows: *1*1, n=14; *1*2, n=8; *1*3, n=2; *2*2, n=l and *2*3, n=1. IBU clearance (CL/F=ml/min/kg) (mean=1.49; range .71-2.59) was significantly correlated to body surface area (r2=0.39; p<.001), body weight (r2=0.36, p=.001), and age (r2=0.31; p=.003). CL/F in subjects with the *1*1 genotype (1.7±0.42) was significantly (p=0.02) greater than that observed in subjects with the *1*2 genotype ( 1.2±0.43). The mean subject age was not different between these subpopulations (e.g., *1*1 = 11.9 yr vs *1*2= 16.9 yr). Stepwise linear regression revealed that BSA (p<0.0001) or age (p=0.004) but not CYP2C9 genotype were significant determinants of IBU CL/F. Conclusion: Variability in the CL/F of IBU in CF is multifactorial and to a great degree is influenced by developmental differences in PK.",
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AU - Murry, D. J.

AU - Kearns, G. L.

AU - Oermann, C.

AU - Gaedigk, A.

AU - Sockrider, M.

AU - Seilheimer, D. K.

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N2 - The PK of IBU (a CYP2C9 substrate) in patients with CF are extremely variable and can be unpredictable. IBU disposition was characterized in 26 patients with CF (5.5 to 29.6 years of age, 16.8-74.6 kg, BSA=0.73-1.93 m2) who received a single oral dose (20.7-27.9 mg/kg) of the drug. IBU was quantitated by HPLC and PK parameters determined by Bayesian estimation. CYP2C9 genotype was determined from leukocyte-derived genomic DNA using PCR RFLP. CYP2C9 genotype distribution was as follows: *1*1, n=14; *1*2, n=8; *1*3, n=2; *2*2, n=l and *2*3, n=1. IBU clearance (CL/F=ml/min/kg) (mean=1.49; range .71-2.59) was significantly correlated to body surface area (r2=0.39; p<.001), body weight (r2=0.36, p=.001), and age (r2=0.31; p=.003). CL/F in subjects with the *1*1 genotype (1.7±0.42) was significantly (p=0.02) greater than that observed in subjects with the *1*2 genotype ( 1.2±0.43). The mean subject age was not different between these subpopulations (e.g., *1*1 = 11.9 yr vs *1*2= 16.9 yr). Stepwise linear regression revealed that BSA (p<0.0001) or age (p=0.004) but not CYP2C9 genotype were significant determinants of IBU CL/F. Conclusion: Variability in the CL/F of IBU in CF is multifactorial and to a great degree is influenced by developmental differences in PK.

AB - The PK of IBU (a CYP2C9 substrate) in patients with CF are extremely variable and can be unpredictable. IBU disposition was characterized in 26 patients with CF (5.5 to 29.6 years of age, 16.8-74.6 kg, BSA=0.73-1.93 m2) who received a single oral dose (20.7-27.9 mg/kg) of the drug. IBU was quantitated by HPLC and PK parameters determined by Bayesian estimation. CYP2C9 genotype was determined from leukocyte-derived genomic DNA using PCR RFLP. CYP2C9 genotype distribution was as follows: *1*1, n=14; *1*2, n=8; *1*3, n=2; *2*2, n=l and *2*3, n=1. IBU clearance (CL/F=ml/min/kg) (mean=1.49; range .71-2.59) was significantly correlated to body surface area (r2=0.39; p<.001), body weight (r2=0.36, p=.001), and age (r2=0.31; p=.003). CL/F in subjects with the *1*1 genotype (1.7±0.42) was significantly (p=0.02) greater than that observed in subjects with the *1*2 genotype ( 1.2±0.43). The mean subject age was not different between these subpopulations (e.g., *1*1 = 11.9 yr vs *1*2= 16.9 yr). Stepwise linear regression revealed that BSA (p<0.0001) or age (p=0.004) but not CYP2C9 genotype were significant determinants of IBU CL/F. Conclusion: Variability in the CL/F of IBU in CF is multifactorial and to a great degree is influenced by developmental differences in PK.

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