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PI-107 EFFECT OF CYP2C8 GENOTYPE ON ROSIGLITAZONE PHARMACOKINETICS. M. W. Hruska, PharmD, J. A. Cheong, MD, J. A. Amico, MD, T. Y. Langaee, MSPH, PhD, R. F. Frye, PharmD, PhD, University of Florida, University of Pittsburgh, Gainesville, FL. BACKGROUND/AIMS: The purpose of this study was to inves- tigate the effect of the CYP2C8 genetic polymorphisms CYP2C8*2, CYP2C8*3, and CYP2C8*4 on the pharmacokinetics of rosiglita- zone, a PPAR agonist and CYP2C8 substrate. METHODS: This single dose pharmacokinetics study involved thirty-eight healthy subjects with the following CYP2C8 genotypes: CYP2C8*1/*1 (n 14), *1/*2 (n 5), *1/*3 (n 11), *1/*4 (n 6), *2/*2 (n 1), and *3/*3 (n 1). Subjects were administered a single dose of rosiglitazone 8 mg. Rosiglitazone concentrations were determined by HPLC and noncompartmental pharmacokinetic pa- rameters were compared between wild type and heterozygous geno- type groups. RESULTS: The pharmacokinetics of rosiglitazone did not differ between CYP2C8 homozygous wild type and heterozygous individ- uals. The mean AUC was 3161625, 3290866, 2928519, and 3230658, gh/L in the *1/*1, *1/*2, *1/*3, and *1/*4 genotype groups, respectively. The subject with the CYP2C8*3/*3 genotype had the second lowest rosiglitazone AUC. CONCLUSIONS: The pharmacokinetics of rosiglitazone were not different in individuals carrying a single variant CYP2C8 allele, as the pharmacokinetic parameters of rosiglitazone did not differ between heterozygous and homozygous wild type individuals. Fur- ther study is needed to determine whether homozygous carriers of the CYP2C8*2 and CYP2C8*3 alleles have altered rosiglitazone phar- macokinetics. PI-108 EFFECT OF GOLDENSEAL, BLACK COHOSH, KAVA KAVA, AND VALERIAN ON HUMAN CYTOCHROME P450 1A2, 2D6, 2E1, AND 3A4 PHENOTYPES. B. J. Gurley, PhD, S. F. Gardner, PharmD, D. K. Williams, PhD, W. B. Gentry, MD, M. A. Hubbard, MS, I. A. Khan, PhD, A. Shah, PhD, University of Arkansas for Medical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, College of Medicine, University of Mississippi, College of Pharmacy, Little Rock, AR. BACKGROUND: Phytochemical-mediated modulation of cyto- chrome P450 activity may underlie many herb-drug interactions. Single time-point, phenotypic metabolic ratios were used to deter- mine whether supplementation of goldenseal, black cohosh, kava, or valerian extracts affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity. METHODS: Twelve healthy volunteers were randomly assigned to receive each supplement for 28 days followed by a 30-day washout period. Probe drug cocktails of midazolam, caffeine, chlorzoxazone, and debrisoquine were administered before and at the end of supple- mentation. Pre- and post-supplementation phenotypic ratios were determined for CYP3A4, CYP1A2, CYP2E1, and CYP2D6 using 1-hydroxymidazolam/midazolam serum ratios (1-hr), paraxanthine/ caffeine serum ratios (6-hr), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hr), and debrisoquine urinary recovery ratios (8-hr), respectively. RESULTS: Comparisons of pre- and post-goldenseal phenotypic ratios revealed significant inhibition (40%) of CYP2D6 and CYP3A4 activity. Black cohosh also inhibited CYP2D6, but the magnitude (7%) did not appear clinically relevant. No significant changes were observed for kava or valerian. CONCLUSIONS: Goldenseal strongly inhibited CYP2D6 and CYP3A4 activity. Accordingly, serious adverse interactions may result if goldenseal is ingested with drugs that are CYP2D6 and CYP3A4 substrates. Kava, black cohosh and valerian appear less likely to produce such interactions. PI-109 INDUCTION OF CYP3A BY ST. JOHNS WORT (SJW) DE- PENDS ON HYPERFORIN (HYF) DOSE. S. C. Mueller, MD, J. Majcher-Peszynska, MD, S. Klammt, MD, B. Uehleke, MD, PhD, W. Miekisch, PhD, G. Kundt, PhD, B. Drewelow, MD, Institute of Clinical Pharmacology, Clinic of Naturopathy, Clinic of Anaesthesi- ology, Institute of Medical Biometry, Rostock, Germany. BACKGROUND: Induction of CYP3A by SJW with high HYF content is known. SJW products vary in the amount of main constit- uents. The aim of the study was to evaluate the influence of SJW preparations with low and high HYF content on CYP3A function. METHODS: A one-sequence crossover study was performed in 42 male, healthy volunteers, who were randomized into 6 SJW groups. Midazolam (MDZ) plasma concentration profiles were char- acterized after a single oral dose of 7.5 mg MDZ on the day before and on the 14 th day of SJW medication. RESULTS: Effect of SJW on % change in MDZ AUC 0 –12h compared to baseline, mean and 95% confidence interval (CI): SJW dose/d (HYF content mg/d) Mean % change 95 %-CI 900mg extract LI 160 (41.25) 79.4 88.6; 70.1 2.7g plant (0.13) 21.1 33.9; 8.3 2.7g plant (12.06) 47.9 59.7; 36.2 1.8g plant (8.04) 37.0 58.2; 15.8 1.2g plant (5.36) 31.3 45.3; 17.3 0.6g plant (2.68) 20.4 40.0; 0.8 Decrease in MDZ AUC was correlated with HYF content (r 0.78, p0.01). CONCLUSION: Induction of CYP3A varies between SJW prod- ucts. SJW products with low HYF content induce CYP3A signifi- cantly less than high HYF SJW products. The degree of induction depends on HYF dose. PI-110 IN VITRO GLUCURONIDATION OF PREDNISONE. F. Inno- centi, MD, PhD, A. Yoder Graber, BA, J. Ramirez, MS, M. J. Ratain, MD, University of Chicago, Chicago, IL. BACKGROUND/AIM: Prednisone is the most commonly pre- scribed immunosuppressant agent, and its metabolites are known to undergo glucuronidation. No data exists on the glucuronidation of unchanged prednisone. We aim to investigate the role of individual UDP-glucuronosyltransferases (UGTs) in prednisone’s direct metab- olism. METHODS: We screened cDNA transfected 1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17. A correlation study was completed with prednisone and a substrate specific for 2B7 (morphine) in human liver microsomes (HLM). Prednisone glucuronide formation was measured by HPLC. RESULTS: The K m of prednisone in HLM was 594118 M (meanSE). Screening showed 2B7 to have 6-fold higher prednisone glucuronidation activity compared to both 1A3 and 2B17. No glucu- ronidation was detected with the other isoforms. Considerable phe- notypic variability was observed in prednisone glucuronidation in HLM (CV61%, n82). There was a significant correlation between prednisone and morphine glucuronidation (r0.66, P0.0001). CONCLUSIONS: Our data suggest 2B7 is the main isoform responsible for prednisone glucuronidation. Future studies in patients receiving prednisone should evaluate the inter-patient variability in prednisone glucuronidation, its clinical relevance, and the role played by 2B7 gene polymorphisms in prednisone therapy. CLINICAL PHARMACOLOGY & THERAPEUTICS P36 American Society for Clinical Pharmacology and Therapeutics FEBRUARY 2005

In vitro glucuronidation of prednisone

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Page 1: In vitro glucuronidation of prednisone

PI-107EFFECT OF CYP2C8 GENOTYPE ON ROSIGLITAZONE

PHARMACOKINETICS. M. W. Hruska, PharmD, J. A. Cheong,MD, J. A. Amico, MD, T. Y. Langaee, MSPH, PhD, R. F. Frye,PharmD, PhD, University of Florida, University of Pittsburgh,Gainesville, FL.

BACKGROUND/AIMS: The purpose of this study was to inves-tigate the effect of the CYP2C8 genetic polymorphisms CYP2C8*2,CYP2C8*3, and CYP2C8*4 on the pharmacokinetics of rosiglita-zone, a PPAR agonist and CYP2C8 substrate.

METHODS: This single dose pharmacokinetics study involvedthirty-eight healthy subjects with the following CYP2C8 genotypes:CYP2C8*1/*1 (n � 14), *1/*2 (n � 5), *1/*3 (n � 11), *1/*4 (n �6), *2/*2 (n � 1), and *3/*3 (n � 1). Subjects were administered asingle dose of rosiglitazone 8 mg. Rosiglitazone concentrations weredetermined by HPLC and noncompartmental pharmacokinetic pa-rameters were compared between wild type and heterozygous geno-type groups.

RESULTS: The pharmacokinetics of rosiglitazone did not differbetween CYP2C8 homozygous wild type and heterozygous individ-uals. The mean AUC was 3161�625, 3290�866, 2928�519, and3230�658, �g�h/L in the *1/*1, *1/*2, *1/*3, and *1/*4 genotypegroups, respectively. The subject with the CYP2C8*3/*3 genotypehad the second lowest rosiglitazone AUC.

CONCLUSIONS: The pharmacokinetics of rosiglitazone werenot different in individuals carrying a single variant CYP2C8 allele,as the pharmacokinetic parameters of rosiglitazone did not differbetween heterozygous and homozygous wild type individuals. Fur-ther study is needed to determine whether homozygous carriers of theCYP2C8*2 and CYP2C8*3 alleles have altered rosiglitazone phar-macokinetics.

PI-108EFFECT OF GOLDENSEAL, BLACK COHOSH, KAVA

KAVA, AND VALERIAN ON HUMAN CYTOCHROME P4501A2, 2D6, 2E1, AND 3A4 PHENOTYPES. B. J. Gurley, PhD, S. F.Gardner, PharmD, D. K. Williams, PhD, W. B. Gentry, MD, M. A.Hubbard, MS, I. A. Khan, PhD, A. Shah, PhD, Universityof Arkansas for Medical Sciences, College of Pharmacy, University ofArkansas for Medical Sciences, College of Medicine, Universityof Mississippi, College of Pharmacy, Little Rock, AR.

BACKGROUND: Phytochemical-mediated modulation of cyto-chrome P450 activity may underlie many herb-drug interactions.Single time-point, phenotypic metabolic ratios were used to deter-mine whether supplementation of goldenseal, black cohosh, kava, orvalerian extracts affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4activity.

METHODS: Twelve healthy volunteers were randomly assignedto receive each supplement for 28 days followed by a 30-day washoutperiod. Probe drug cocktails of midazolam, caffeine, chlorzoxazone,and debrisoquine were administered before and at the end of supple-mentation. Pre- and post-supplementation phenotypic ratios weredetermined for CYP3A4, CYP1A2, CYP2E1, and CYP2D6 using1-hydroxymidazolam/midazolam serum ratios (1-hr), paraxanthine/caffeine serum ratios (6-hr), 6-hydroxychlorzoxazone/chlorzoxazoneserum ratios (2-hr), and debrisoquine urinary recovery ratios (8-hr),respectively.

RESULTS: Comparisons of pre- and post-goldenseal phenotypicratios revealed significant inhibition (40%) of CYP2D6 andCYP3A4 activity. Black cohosh also inhibited CYP2D6, but themagnitude (7%) did not appear clinically relevant. No significantchanges were observed for kava or valerian.

CONCLUSIONS: Goldenseal strongly inhibited CYP2D6 andCYP3A4 activity. Accordingly, serious adverse interactions mayresult if goldenseal is ingested with drugs that are CYP2D6 andCYP3A4 substrates. Kava, black cohosh and valerian appear lesslikely to produce such interactions.

PI-109INDUCTION OF CYP3A BY ST. JOHNS WORT (SJW) DE-

PENDS ON HYPERFORIN (HYF) DOSE. S. C. Mueller, MD, J.Majcher-Peszynska, MD, S. Klammt, MD, B. Uehleke, MD, PhD, W.Miekisch, PhD, G. Kundt, PhD, B. Drewelow, MD, Institute ofClinical Pharmacology, Clinic of Naturopathy, Clinic of Anaesthesi-ology, Institute of Medical Biometry, Rostock, Germany.

BACKGROUND: Induction of CYP3A by SJW with high HYFcontent is known. SJW products vary in the amount of main constit-uents. The aim of the study was to evaluate the influence of SJWpreparations with low and high HYF content on CYP3A function.

METHODS: A one-sequence crossover study was performed in42 male, healthy volunteers, who were randomized into 6 SJWgroups. Midazolam (MDZ) plasma concentration profiles were char-acterized after a single oral dose of 7.5 mg MDZ on the day beforeand on the 14th day of SJW medication.

RESULTS: Effect of SJW on % change in MDZ AUC 0–12hcompared to baseline, mean and 95% confidence interval (CI):

SJW dose/d(HYF content mg/d) Mean % change 95 %-CI

900mg extract LI 160 (41.25) �79.4 �88.6; �70.12.7g plant (0.13) �21.1 �33.9; �8.32.7g plant (12.06) �47.9 �59.7; �36.21.8g plant (8.04) �37.0 �58.2; �15.81.2g plant (5.36) �31.3 �45.3; �17.30.6g plant (2.68) �20.4 �40.0; �0.8

Decrease in MDZ AUC was correlated with HYF content (r ��0.78, p�0.01).

CONCLUSION: Induction of CYP3A varies between SJW prod-ucts. SJW products with low HYF content induce CYP3A signifi-cantly less than high HYF SJW products. The degree of inductiondepends on HYF dose.

PI-110IN VITRO GLUCURONIDATION OF PREDNISONE. F. Inno-

centi, MD, PhD, A. Yoder Graber, BA, J. Ramirez, MS, M. J. Ratain,MD, University of Chicago, Chicago, IL.

BACKGROUND/AIM: Prednisone is the most commonly pre-scribed immunosuppressant agent, and its metabolites are known toundergo glucuronidation. No data exists on the glucuronidation ofunchanged prednisone. We aim to investigate the role of individualUDP-glucuronosyltransferases (UGTs) in prednisone’s direct metab-olism.

METHODS: We screened cDNA transfected 1A1, 1A3, 1A4,1A5, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17. Acorrelation study was completed with prednisone and a substratespecific for 2B7 (morphine) in human liver microsomes (HLM).Prednisone glucuronide formation was measured by HPLC.

RESULTS: The Km of prednisone in HLM was 594�118 �M(mean�SE). Screening showed 2B7 to have 6-fold higher prednisoneglucuronidation activity compared to both 1A3 and 2B17. No glucu-ronidation was detected with the other isoforms. Considerable phe-notypic variability was observed in prednisone glucuronidation inHLM (CV�61%, n�82). There was a significant correlation betweenprednisone and morphine glucuronidation (r�0.66, P�0.0001).

CONCLUSIONS: Our data suggest 2B7 is the main isoformresponsible for prednisone glucuronidation. Future studies in patientsreceiving prednisone should evaluate the inter-patient variability inprednisone glucuronidation, its clinical relevance, and the role playedby 2B7 gene polymorphisms in prednisone therapy.

CLINICAL PHARMACOLOGY & THERAPEUTICSP36 American Society for Clinical Pharmacology and Therapeutics FEBRUARY 2005