C L I N I C A L P H A R M A C O L O G Y & T H E R A P E U T I C S

VOLUME 73, NUMBER2 American Society for Clinical Pharmacology and Therapeutics P 7 5

PIII -47 COVARIATES PREDICT MEDICATION DISCREPANCIES

AFTER THERAPEUTIC SUBSTITUTION (TS). J.F. Graumlich, MD, N.L. Novotny, MS, L.J. Cation, MD, S.L. Rusch, MD, J.C. Aldag, PhD. University of Illinois College of Medicine, OSF Saint Francis Medical Center, Peoria, IL.

Purpose: Identify covariates for post-discharge medication dis- crepancies after in-patient TS. Methods: Adult cohort interviewed within 3 weeks after in-patient TS of a proton pump inhibitor (PPI), HMG-CoA reductase inhibitor, or angiotensin-converting enzyme inhibitor. One TS drug matched 1 random control drug from dis- charge list. Discrepancy (y/n) between discharge prescription and telephone interview drugs was analyzed by discrepancy type and covariate. Results: N=301. NS not significant. Polyph = poly- pharmacy

Patients, n (%) McNemar

TS Contrl P value

Odds Ratio for Covariates Type of drug discrepancy Sex Polyph PPI Pre

Different in class 32(11) 2(1) <0.00l 2.84 NS NS 0.042 No chug in class 30(10) 19(6) 0.118 2.41 0.16 2.57 NS

Conclusion: TS, female, and Pre (pre-admission drug = discharge drug) predict discrepancy: different drug in same class. Female, potypharmacy, and TS with PPI, predict the "no drug within class" discrepancies.

PIII -48 PPAR GAMMA ACTIVATION RAPIDLY INCREASES

ACRP30 IN NON-DIABETIC SUBJECTS. J. A. Wagner, MD, PhD, M. E. Flynn, A. Knops, MD, A. H. Hartford, PhD, A. L. Dallob, MS, W. K. Tanaka, PhD, M. DeSmet, PhD, K. Van Dyck, PhD, C. Stevens, RN, P. E. Scherer, PhD, K. M. Gottesdiener, MD, Merck & Co., Inc., SGS Biopharma, Albert Einstein College of Medicine, Railway, NJ.

Circulating adipocyte complement-related protein 30 kDa (ACRP30; adiponectin) levels are increased by peroxisome proliferator-activated receptor (PPAR) 3, agonists in diabetic and nondiabetic humans and, thus, may serve as a biomarker for PPARy agonist activity. Methods: We assessed ACRP30 before and after double-blind treatment with placebo (P) and rosiglitazone (R; 4 mg bid) for 14 days in healthy, nondiabetic volunteers (N= 10/group). A polyclonal antibody to ACRP30 was used to measure plasma levels by quantitative Western blot analysis. Results: ACRP30 levels rose rapidly following R treatment. By Day 4 and throughout the remain- der of treatment, there was a statistically significant increase in ACRP30

80 ill c 70

-~ 60

m 50

g~ 40 O ~ O ~ m,, 30 EL +1

20

10

0 E

¢ - 2 0 13_

-30

levels in R- versus P-treated subjects.

Baseline Mean (_+SE) Placebo: 0.5 _+ 0.1 1 units/~L

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Treatment Day

• Placebo (n=10) • Rosigtitazone 4mg BID (n=10)

Conclusion: Since reduced ACRP30 mRNA expression is asso- ciated with insulin-resistance in animals and humans, the protein is efficacious in reducing postprandial glucose levels in vivo in animal models of diabetes, and ACRP30 levels rise rapidly after rosiglita- zone treatment in nondiabetic subjects, we speculate that ACRP30 may be implicated in the insulin-sensitizing action of PPARy ago- nists in patients with type 2 diabetes.

PIII -49

IMPACT OF THE CYP2C9 AND CYP2D6 POLYMORPHISMS FOR PHARMACOKINETICS OF 3R,5S- AND 3S,5R FLUVA- STATIN. J. Kirchheiner, MD, D. Kudlicz, C. Meisel, MD, I. Roots, Prof. MD, J. BrockmOller, Prof. MD, Institute of Clinical Pharma- cology, Charit6, Department of Clinical Pharmacology, Berlin, Ger- many.

We measured kinetics of 3R,5S- and 3S,5R fluvastatin a single dose of 40 mg in 25 healthy volunteers selected as heterozygous and homozygous carriers of the CYP2C9 variants Argl44Cys (*2) and Ile359Leu (*3) and in 3 CYP2D6 poor metabolizers. Plasma choles- terol was measured after continued intake of 40 mg fluvastatin over 14 days. Mean (÷ SD) racemic fluvastatin AUCs (sum of the enan- tiomers) were 4-fold higher in carriers of two CYP2C9"3 alleles compared to carriers of the wild type genotype CYP2C9*I/*I with values of 1430 (-+ 316) versus 345 (2 223) v~g L-1 h; (p <0.001). Heterozygotes were in between with 605 (_+ 2l 1) txg L-1 h, whereas allele *2 did not exhibit any effect. Elimination half-life was pro- longed in carriers of CYP2C9"3/ '3 versus CYP2C9*I/*I (1.2 (-+ 0.4) and 0.7 (2 0.4) h, respectively) and the same effect was seen for maximal plasma concentrations (735 -+ 147 versus 278 _+ 160 ixg L-l, (p=0.001) indicating contribution of CYP2C9 to first pass metabolism. CYP2C9 influence was shnilar for both enantiomers. Deficient CYP2D6 was not associated with diminished fluvastatin clearance. All individuals had slight decreases in plasma cholesterol after 14 days of fluvastatin intake. In conclusion, homozygous and heterozygous carriers of CYP2C9 allele *3 had significantly higher plasma concentrations than the remaining 85% of the population, and they may experience more effective therapeutic improvement but also they may be at higher risk for myopathy or hepatotoxicity.

P I I I - 5 0

COMPARISON OF THE IMPACT OF THE CYP2C9 GENO- TYPE ON THE PHARMACOK1NETICS AND PHARMACODY- NAMICS OF THE NSAIDS CELECOXIB, DICLOFENAC, AND IBUPROFEN. J. Kirchheiner, MD, I. Meineke, PhD, I. Roots, MD, J. Brockm611er, MD, Institute of Clinical Pharmacology, Charit6, Department of Clinical Pharmacology, Berlin, Germany.

In vitro data indicated metabolisms of most nonsteroidal antiin- fiammatory drugs (NSAID) by the genetically polymorphic cyto- chrome P450 enzyme 2C9 (CYP2C9). We measured single-dose kinetics of 600 mg ibuprofen, 100 mg celecoxib and 50 mg diclofe- nac in 21 healthy volunteers who were selected as hetero- and homozygous carriers of CYP2C9 variants Arg144Cys (*2) and Ile359Leu (*3). Blood concentrations of tbromboxane B2 (TXB2) and prostaglandin E2 (PGE2) reflecting inhibition of cyclooxygen- ases (COX) 1 and 11 were quantified. A more than twofold reduced oral clearance in homozygous carriers of CYP2C9"3 was seen for celecoxib and ibuprofen, whereas CYP2C9"2 had only marginal influence for both NSAIDs. Metabolism of diclofenac was not in any kind different between the CYP2C9 genotypes. TXB2 and PGE2- concentrations were suppressed after ibuprofen and diclofenac intake and inhibition was significantly more prolonged in CYP2C9"3/ '3 after ibuprofen-intake compared with carriers of the other CYP2C9 genotypes. Thus, ibuprofen and celecoxib, but not diclofenac are largely affected by the CYP2C9 genotype with "1/ '3 representing a slow and "3/ '3 a very slow or poor metabolizer phenotype. In in-vitro versus in-vivo discrepancy with respect to diclofenac cannot be completely resolved with our data; however, this clearly illustrates the importance of focussed clinical trials in pharmacogenefics.