Background IBDs are chronic, recurrent diseases which need long-term treatment. We conducted a phase I clinical trial of DA-6034, an extractor of wormwood, to evaluate the tolerability, safety, and PK of this compound. Methods A double-blind, dose randomized, placebo-controlled, dose-rising study was conducted in 67 healthy volunteers. The volunteers were randomly allocated to single-dose groups of 10mg, 20mg, 50mg, 100mg, and 200mg (8 per dose including 2 placebos) or multiple-dose groups of 20mg, 50mg, and 100mg (twice-daily dosing for 7 days; 9 per dose including 3 placebos). After dosing serial blood and urine samples were taken. Drug concentrations were determined by HPLC assay. Assessments of safety and tolerability were made. Results The Cmax of DA-6034 was very low (2.52±1.47ng/mL in 200mg group). Four subjects taking active drugs of 10mg, 20mg, and 50mg group showed that plasma concentrations were below the LLQ at all time points. Urinary cumulative amount of excretion to 48 hour after dosing was 0.3%. No serious adverse effects were observed. Conclusions DA-6034 was little absorbed in healthy volunteers, as expected from the preclinical data. The target organ is the GI tract, so the PK of DA-6034 which was little absorbed to systemic circulation and was localized in the GI tract is expected to be advantageous for patients. However, it is possible that in patients the absorption pattern is altered by inflammation, so further evaluation of the PK along with efficacy of DA-6034 in IBD patients is expected. Clinical Pharmacology & Therapeutics (2005) 77, P57–P57; doi: 10.1016/j.clpt.2004.12.106

Background CYP2C9, CYP2J2, and sEH have been shown to be involved in the formation and metabolism of vasoactive epoxides of the epoxygenase pathway which have been proposed to play a role in the pathogenesis of hypertension and progression of renal failure. The AA population with endstage renal disease (ESRD) on HD has a high prevalence of hypertension and may have altered prevalence of these polymorphisms Methods We studied the frequency of CYP2C9*8 and *11, sEH R287Q and anR403insertion, and CYP2J2*2-*7 and the newly identified CYP2J2 polymorphisms R49S, L50L, V113M, N124S in 97 AA ESRD patients and 84 healthy AA to determine whether there is a significant difference in prevalence rates of these polymorphisms. The mean age of the ESRD patients was 53.3± 12.1 years (mean± sd) and the healthy AA was 38.6± 9.1 years. The ESRD patients and healthy subjects were 43.3% and 38.6 % female, respectively. The DNA was isolated from peripheral blood mononuclear cells and then genotyped for the variant alleles using TaqMan-based allelic discrimination assays. Results The prevalence of the CYP2J2 variant alleles with the exception of CYP2J2*7 (see Table) ranged from 0 to 1.1% in the healthy and ESRD populations. Additional results are shown in the table below. Conclusions There was no significant difference in prevalence rates of the CYP2C9, CYP2J2, and sEH alleles in AA with ESRD compared with the healthy AA population. This is similar to the results we previously reported for CYP2C9*2–5 and CYP2C8*2-*3. Clinical Pharmacology & Therapeutics (2005) 77, P57–P57; doi: 10.1016/j.clpt.2004.12.108 Prevalence of Epoxygenase SNPs In AA on HD Allele ESRD (%) N = 97 Healthy (%) N = 101 P Chi-Square CYP2C9*8 4.6 3.0 NS CYP2C9*11 2.1 1.0 NS sEH R287Q 10.8 8.0 NS sEH R403ins 0 2.0 NS CYP212*7 8.5 11.1 NS