CLINICAL PHARMACOLOGY & THE1LAPEUTICS P 7 6 American Society for Clinical Pharmacology and Therapeutics ~Em~u~Y2003

PIII-51 INFLUENCE OF CYP2C9 AMINO ACID POLYMORPHISMS

ON ENANTIOSELECTIVE METABOLISM OF R-,S- PHENPROCOUMON. I. Roots, MD: J. Kirchheiner, MD, E. Walter, MS, B. Kammerer, PhD, M. Schwab, MD, C. Meisel, MD, J. Brockm61ler, MD, Humboldt University Berlin, Charite Medical Center, University Ttibingen, Dr. Margarete Fischer Bosch Institute of Clinical Pharmacology, Georg August University G/Sttingen, Ber- lin, Germany.

CYP2C9 catalyzes biotransformation of the vitamin K antagonist S-warfarin and acenocoumarol; individuals homozygous for CYP2C9"3 are at high risk for bleeding complications. In vitro studies indicated that the related S-phenprocoumon may be a CYP2C9 substrate as well. We studied phenprocoumon plasma con- centrations after a single-dose of 12 mg in healthy volunteers selected according to their CYP2C9 genotype. No statistically significant influence of the common CYP2C9 potymorphisms CYP2C9"3 and CYP2C9"2 on S-phenprocoumon plasma concentrations were de- tected in homozygous and heterozygous carriers, but a trend towards higher mean AUCs in individuals with CYP2C9 variants *2 and *3 was apparent with AUC data of 125, 134, 163, t72, 263, and 173 mg'L-I'h for CYP2C9 genotypes "1/'1, "1/'2, *2, *2, "1/'3, *2/*3, *3/*3, respectively, with standard deviations of 36, 40, 64, 126, 125, and 6 mg'L-l'h, respectively. No difference in the kinetic parameters of R-phenprocoumon were detected when comparing the 6 studied CYP2C9 genotypes. Thus, in contrast to S-warfarin, CYP2C9 is not the dominant enzyme of phenprocoumon metabolism in vivo. With regard to bleeding complications, phenprocoumon might even be safer than warfarin or acenocoumarol in individuals carrying low activity variants of CYP2C9; however, pharmacoepidemiological studies thus far do not indicate that phenprocoumon is more safe than S-warfarin in general.

PIII-52 IMPACT OF CYP2C9 AMINO ACID VARIANTS Arg144Cys

AND Ile359Leu ON THE PHARMACOKINETICS AND PHAR- MACODYNAMICS OF NATEGLINIDE. J. Brockm611er, MD, J. Kirchheiner, MD, G. Mfiller, MS, I. Meineke, PhD, C. Meisel, MD, I. Roots, MD, Georg-August University G6ttingen, Humboldt Uni- versity Berlin, Georg August University G6ttingen, G6ttingen, Ger- many.

The new meglitinide class oral antidiabetic drug nateglinide is metabolically inactivated by CYP2C9 and CYP3A4 and about 15% is eliminated as unchanged drug via the kidneys. Here we wanted to study the impact of two CYP2C9 amino acid variants on nateglinide phamlacokinetics and on nateglinide pharmacodynamic effects mea- sured as plasma glucose, plasma insulin and glucagon. Drug concen- trations, blood glucose, insulin and ghicagon concentrations were measured after intake of 180 mg nateglinide under glucose challenge with 75 g oral glucose 0, 4 and 8 h after nateglinide intake. A two-fold reduced mean (SD) oral clearance was observed in homozy- gous carriers of CYP2C9"3 compared with the wild type genotype CYP2C9"1/'1 with clearances of 3.9 (_+0.3) versus 8.4 (± 1.7) L-h -1. Heterozygotes with the genotype CYP2C9"1/'3 were in between with a clearance of 6.9 (-+ 1.4) L.h 1. (p=0.01 for gene-dose depen- dent trend). No significant effects of the Arg144Cys variant CYP2C9"2 were found. The pharmacokinetic differences caused by the CYP2C9 polynaorphism were not reflected in the plasma glucose, insulin or glucagon concentration-time profiles. In conclusion, carri- ers of the CYP2C9"3 had unambiguously a lower nateglinide clear- ance but the difference was only moderate and was not reflected in glucose or insulin concentrations. The overall low pharmacokinetic variability is probably explained by the three routes of nateglinide elimination.

PIII-53 PHARMACOGENETIC-PHARMACOKINETIC RELATION-

SHIPS FOR DESIPRAMINE. D. A. Katz, PhD, K. D. Furman, D. R. Grimm, PhD, R. J. Bertz, PhD, Abbott Laboratories, Abbott Park, IL.

Desipramine is a well-known CYP2D6 probe substrate. In an interaction study utilizing desipramiue as a 'target', genotyping was used to screen out CYP2D6 poor metabolizers. Still, there was substantial variability of desipramine pharmacokinetics in the screened population. Two interesting relationships between CYP2D6 genotype and pharmacokinetic parameters were observed. First, an individual who had unusually high elimination half-time, exposure and metabolic ratios, and low clearance, can'ied a partially functional *9 allele in combination with a non-functional allele. This combina- tion has a population frequency of less than t/200. Second, individ- uals who are genotypically *1/*1, "1/'41 and "41/ '41 had lower than average elimination half-time, exposure and metabolic ratios, and higher than average clearance. Individuals who are genotypically "1 / '2 and *2/*2 had pharmacokinetic parameters across a much broader range. For desipramine, the distinction between *2 and "41 carriers helps to define two subgroups of the extensive metabolizer cohort.

PIII-54 THE HEAT-STABLE ENTEROTOXIN RECEPTOR, GUANY-

LYL CYCLASE C (GC-C), IS A MOLECULAR MARKER FOR UPPER AND LOWER GASTROINTESTINAL MALIGNANCIES. S. Schulz, PhD, K. Nielsen, R. Birbe, MD, R. Walters, J. Palazzo, MD, S. A. Waldman, MD, PhD, Thomas Jefferson University, Phil- adelphia, PA.

GC-C is normally expressed exclusively by intestinal epithelial cells from the duodenum to the rectum, and this expression persists following neoplastic transformation to colorectal cancer. Also, GC-C is expressed de novo in intestinal metaplasia, a common precursor to adenocarcinomas of the esophagus and stomach. A quantitative RT- PCR (QRT-PCR) assay for detecting GC-C mRNA as a tumor marker was developed using GC-C-specific primers and a Taq-Man probe with the ABI 7000 Sequence Detection System. Employing an in vitro transcribed GC-C standard, this assay was linear over 5 orders of magnitude, with a limit of detection of - 1 0 0 molecules. Pah'ed surgical samples were analyzed by both QRT-PCR and histopathol- ogy. GC-C mRNA was over-expressed in colorectal tumors, com- pared to normal intestine, and this was confirmed by immunohisto- chemistry employing a GC-C-specific antiserum. Similarly, GC-C mRNA was detected in intestinal metaplasia and adenocarcinomas of the esophagus and stomach, which was confirmed by immunohisto- chemistry. Additionally, GC-C mRNA and protein were detected in all lymph nodes that contained metastatic colon cancer by histopa- thology. Significantly, GC-C was detected by QRT-PCR and immu- nohistochemistry in lymph nodes that were apparently free of disease by histopathology. Thus, GC-C may be a sensitive and specific marker for staging colorectal cancer, as well as an early marker for pre-neoplastic changes in the upper GI tract.