CLINICAL PHARMACOLOGY & THERAPEUTICS VOLUMe 73, NUMBER2 American Society for Clinical Pharmacology and Therapeutics P 9 7

PDII-C-2 VARIABILITY IN THIOPURINE METHYLTRANSFERASE

(TPMT) AND OUTCOME IN PEDIATRIC RENAL TRANS- PLANT PATIENTS. J .A. Lowr,/, MD, A. Gaedigk, PhD, L. Reed, RN, J. S. Leeder, PhD, PharmD, D. Blowey, MD, Children's Mercy Hospital, Kansas City, MO.

TPMT is a genetically polymorphic enzyme responsible for the metabolic inactivation of azathioprine, an immunosuppressive agent used in renal transplant patients to prevent rejection. The goal of this study was to determine the relationship between TPMT genotype and adverse outcomes. Methods: Children who received a renal trans- plant were consented for the study. A retrospective chart review was performed for demographic data and laboratory values (WBC, he- moglobin, platelets, serum creatinine), azathioprine dose, and rejec- tion episodes. DNA was isolated from buccal swabs and/or blood obtained from clinic visits. TPMT '1 , *2, *3, *4, *5 and *6 alleles were assessed using a PCR-RFLP based genotyping procedure. Re- suits: Consent was obtained from 34 renal transplant patients; DNA was available from buccal or blood samples for 31 (5 female, 26 male). Age at transplant ranged from 7 months to 16 years. Twenty- five were found to be homozygous wild type, while 6 were heterozy- gous. None were carriers of 2 mutant alleles. No difference in rejection episodes in the first year was noted between homozygous and heterozygous patients (p=0.30) nor in adverse events such as immunosuppression, anemia, thrombocytopenia, or hepatotoxicity. Conclusion: TPMT genotype corresponding to the extensive or in- termediate phenotype does not appear to account for adverse effects observed with renal transplant patients treated with azathioprine.

PDII-C-4 PHARMACOGENETIC DETERMINANT OF CYCLOPHOS-

PHAMIDE THERAPY IN PATIENTS WITH LUPUS NEPHRITIS. M. Arefagene, MSc, Z. Desta, PhD, K. Takada, PhD, C. Yarboro, PhD, H. Carrero, PhD, G. Illei, PhD, D. A. Flockhart, MD, PhD, IUPUI, indianapolis, IN.

We tested the hypothesis that genetic variants of cytochrome P450s involved in cyclophosphamide (CY) metabolism modify CY clinical response in patients with lupus nephritis (LN). We genotyped CYP2B6 ( '5), CYP2C19 (*2 and *3) and CYP2C9 (*2 and *3) genes in 60 patients with diffuse proliferative LN who was previously treated with CY at the NIAMS. We then tested the association of these data with appropriate clinical endpoints of efficacy and toxicity: achievement of complete renal response (CR); doubling of serum creatinine; and development of end-stage renal disease (ESRD) and of premature ovarian failure (POF). In a Kaplan-Meier survival analysis, patients homozygous for the variant alleles for CYP2B6*5 (n=3) and for CYP2C19"2 (n=4) had higher probability of doubling of creatinine (P = 0.0018) or reaching ESRD (P =0.0001), and showed a trend towards lower likelihood of achieving CR (P=0.0535). None of the patients who were homozygous for the wild type alleles (N = 26) developed ESRD (P=0.0281). A logistic regression analysis revealed that patients who were carriers of CYP2C19"1/ '2 or CYP2C19"2/ '2 had a significantly lower risk of developing POF (odds ratio: 0.064, 95% CI of 012 to 0.343) after adjustment for age at the initiation of CY treatment and total doses of CY received. Genotyping for CYP2C19 and CYP2B6 may be a valuable adjunct to clinical predictors of outcome in LN patients treated with CY.

PDII-C-3 BETA-I ADRENORECEPTOR GENRE HAPLOTYPES AND

ANTIHYPERTENSIVE RESPONSE TO BETA-BLOCKER THER- APY. I. Zineh, PharmD, B. J. Puckett, PharmD, D. F. Panly, MD, PhD, S. P. McGorray, PhD, J. A. Johnson, PharmD, University of Florida College of Pharmacy, University of Florida College of Med- icine, Gainesville, FL.

Haplotypes may be more powerful than single nucleotide poly- morphisms (SNPs) in predicting drug response. We have previously shown codon 389 genotype of the ~31-adrenoreceptor (131AR) to be a predictor of blood pressure (BP) response to [3-blockers. Here, we examine the impact of [31AR haplotype on BP response to metopro- lol.

Forty hypertensives (untreated clinic DBP -> 95) aged 35 to 65 underwent baseline 24h ambulatory BP monitoring (ABPM), fol- lowed by metoprolol 50 mg bid titrated to response or 200 mg bid. After --> 4 weeks at stable dose, 24h ABPM was repeated. Codon 49 and 389 genotypes were determined by PCR and RFLP. Since we previously demonstrated that the G1y49/Gly389 haplotype did not occur among 1254 alleles, haplotypes could be confidently assigned.

There were no differences in baseline DBP between groups (p = 0.12). B P response by haplotype is shown in the Table. Response was significantly associated with [31AR haplotype. Haplotype was more informative than codon 389 genotype alone. For example, BP response in Arg389 homozygotes (coIumns 1 and 2) was modified by codon 49 genotype.

SR/SR SR/GR SR/SG GR/SG (n=12) (n=6) (n=15) (n=7)

DPBB-DBP T (mmHg) -14.7" -8.8 -5.9 -0.5

DBPB-DBPT = A in DBP from baseline to treatment. *p=0.006 between groups. SR=Ser49Arg389; SG=Ser49Gly389; GR=Gly49Arg389.

131AR haplotype is a more useful predictor of BP response to metoprolol than single SNP genotype. This is one of only a few studies examining association between haplotype and variation in drug response.

PDII-C-5 IDENTIFICATION OF A NEW BETA1-ADRENERGIC RE-

CEPTOR VARIANT VAL5ALA MORE FREQUENT IN AFRICAN-AMERICANS. H.C. Prasad, MD, PhD, R. B. Kim, MD, A. J. J. Wood, MD, C. M. Stein, MD, Dept. Medicine and Pharma- cology, Vanderbilt Univ. School of Medicine, Nashville, TN.

There are marked ethnic differences in drug response to Betal- adrenergic receptor (Betal-AR) blockade with African-Americans being less, and Chinese more sensitive than Caucasians. Only two common coding region polymorphisms Arg389Gly and Ser49Gly have been described. Therefore, we sought to systematically identify all common variants of the human Betal-AR gene. We sequenced the 5 'UTR and coding sequence of the Betal-AR in 3 major ethnic groups, Blacks (n = 50), Whites (n = 50), and Asians (n = 30). The allele frequency of the Betal-AR Gly389 variant was significantly higher in African-Americans (51%) than Caucasians (34%)(P = 0.02) and Asians (22%) (P < 0.0001). The allele frequency of the Betal-AR Gly49 variant did not differ among Blacks (14%), Whites (9%) and Asians (15%)(P for all >0.3). A novel Betal-AR variant, Val5Ala was identified in African-Americans (3%) but not in Whites and Asians. The Val5Ala variant is located in the amino-terminus of the Betal-AR, an area important for receptor localization in the cell membrane and trafficking, and may therefore have functional impor- tance.