modeling circadian rhythm of diastolic blood pressure in hypertensive patients using 24-hour...
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PII-21EVALUATION OF PHARMACOKINETIC CHARACTERIS-
TICS OF A NOVEL ANTI-IBD DRUG, DA-6034, IN HEALTHYVOLUNTEERS. K. S. Lim, MD, J. Y. Chung, MD, J. R. Kim, MD,H. R. Jung, RPh, J. Y. Cho, PhD, K. S. Yu, MD, PhD, M. W. Son,PhD, J. Y. Chung, I. J. Jang, MD, PhD, S. G. Shin, MD, PhD, SeoulNational University Hospital, DongA Pharm. Co. Ltd, Seoul, Repub-lic of Korea.
BACKGROUND: IBDs are chronic, recurrent diseases whichneed long-term treatment. We conducted a phase I clinical trial ofDA-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 of10mg, 20mg, 50mg, 100mg, and 200mg ( 8 per dose including 2placebos) 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 con-centrations were determined by HPLC assay. Assessments of safetyand tolerability were made.
RESULTS: The Cmax of DA-6034 was very low(2.52�1.47ng/mL in 200mg group). Four subjects taking activedrugs of 10mg, 20mg, and 50mg group showed that plasma concen-trations were below the LLQ at all time points. Urinary cumulativeamount of excretion to 48 hour after dosing was 0.3%. No seriousadverse effects were observed.
CONCLUSIONS: DA-6034 was little absorbed in healthy volun-teers, as expected from the preclinical data. The target organ is the GItract, so the PK of DA-6034 which was little absorbed to systemiccirculation and was localized in the GI tract is expected to beadvantageous for patients. However, it is possible that in patients theabsorption pattern is altered by inflammation, so further evaluation ofthe PK along with efficacy of DA-6034 in IBD patients is expected.
PII-22IMPACT OF GENETIC POLYMORPHISMS IN THE GENE
CODING FOR SODIUM POTASSIUM DICHLORIDE COTRANS-PORTER (NKCC2) AND SERUM GLUCOCORTICOID KINASE(SGK1) FOR PHARMACODYNAMICS OF FUROSEMIDE. D.Sehrt, MD, S. Vormfelde, MD, M. Toliat, PhD, P. Nurnberg, PhD, M.Schirmer, MD, J. Brockmoller, MD, University of Gottingen, Max-Delbruck-Centre, Gottingen, Germany.
BACKGROUND /AIMS: We were interested whether the knowninter-individual variability in furosemide effects might be relatedwith genetic polymorphisms in the sodium potassium dichloridecotransporter (NKCC2) and in serum and glucocorticoid regulatedkinase (SGK1) which regulates NKCC2.
METHODS: In an open-label single dose study 93 healthy malevolunteers received a single dose of 80 mg furosemide. Urine vol-ume, sodium, chloride, potassium and calcium excretion was mea-sured in 9 intervals between 0 and 24 hours after drug administration.
RESULTS: A total of 10 informative polymorphisms in theNKCC2 gene were analyzed but none of them was significantlyassociated with the furosemide effects. However, one intronicallylocalized guanine/deletion (G/del) polymorphism in the SGK1 genewas associated with Na, Cl, K, and Ca urinary excretion. Na excretionin the first 3 hours after furosemide was 198, 247, and 273 mmol inG/G, G/del and del/del, respectively (p�0.002, ANOVA). Thisgenotype-related difference was also seen in the cumulative 24-hoururine. Correspondingly, Cl excretion was also correlated with theSGK1 polymorphism (p � 0.001 for the 3 h interval) and there werealso differences in K and Ca excretion. We did however not observesignificant influences on the urine volumes.
CONCLUSIONS: The finding with SKG1 might have great med-ical relevance but requires further confirmation because of the ex-plorative nature of our investigation.
PII-23THE PREVALENCE OF CYP2C9, 2J2, AND SOLUBLE EPOX-
IDE HYDROLASE (SEH) POLYMORPHISMS IN AFRICAN-AMERICANS (AA) ON HEMODIALYSIS (HD). A. W. Dreisbach,MD, S. Japa, PhD, A. Sigel, BS, M. B. Parenti, BSRN, A. E. Hess,BA, S. Srinnouanprachanh, BS, F. M. Farin, MD, A. E. Rettie, PhD,J. J. Lertora, MD, PhD, Tulane University Medical School, Univer-sity of Washington, New Orleans, LA.
BACKGROUND: CYP2C9, CYP2J2, and sEH have been shownto be involved in the formation and metabolism of vasoactive epox-ides of the epoxygenase pathway which have been proposed to playa role in the pathogenesis of hypertension and progression of renalfailure. The AA population with endstage renal disease (ESRD) onHD has a high prevalence of hypertension and may have alteredprevalence of these polymorphisms
METHODS: We studied the frequency of CYP2C9*8 and *11, sEHR287Q and anR403insertion, and CYP2J2*2-*7 and the newly identifiedCYP2J2 polymorphisms R49S, L50L, V113M, N124S in 97 AA ESRDpatients and 84 healthy AA to determine whether there is a significantdifference in prevalence rates of these polymorphisms.The mean age ofthe ESRD patients was 53.3 � 12.1 years (mean � sd) and the healthyAA was 38.6 � 9.1 years. The ESRD patients and healthy subjects were43.3% and 38.6 % female, respectively. The DNA was isolated fromperipheral blood mononuclear cells and then genotyped for the variantalleles using TaqMan-based allelic discrimination assays.
RESULTS: The prevalence of the CYP2J2 variant alleles with theexception of CYP2J2*7 (table) ranged from 0 to 1.1% in the healthy andESRD populations. Additional results are shown in the table below.
Prevalence of Epoxygenase SNPs In AA on HD
AlleleESRD (%)
N � 97Healthy (%)
N � 101P
Chi-Square
CYP2C9*8 4.6 3.0 NSCYP2C9*11 2.1 1.0 NSsEH R287Q 10.8 8.0 NSsEH R403ins 0 2.0 NSCYP212*7 8.5 11.1 NS
CONCLUSIONS: There was no significant difference in prevalencerates of the CYP2C9, CYP2J2, and sEH alleles in AA with ESRDcompared with the healthy AA population. This is similar to the resultswe previously reported for CYP2C9*2–5 and CYP2C8*2-*3.
PII-24MODELING CIRCADIAN RHYTHM OF DIASTOLIC BLOOD
PRESSURE IN HYPERTENSIVE PATIENTS USING 24-HOURAMBULATORY BLOOD PRESSURE MONITORING. H. Lee,MD, PhD, D. Yim, MD, PhD, B. Green, PharmD, PhD, C. Peck, MD,PhD(hon.), Center for Drug Development Science, GeorgetownUniversity, Washington, DC.
BACKGROUND: To develop a model describing the circadianrhythm of the 24-hour ambulatory blood pressure monitoring(ABPM) measured diastolic blood pressure (DBP) in patients withmild to moderate essential hypertension when no drug is present.
METHODS: 3,771 ABPM measurements from 107 hypertensivepatients in a randomized placebo-controlled study of an antihyper-tensive agent, assigned to the placebo group (n�24, 3 occasions) orin the placebo run-in period (n�83), were analyzed by nonlinearmixed effects regression using NONMEM. FOCE with interactionwas the estimation method.
RESULTS: The final model was a two-cosine term model (24-and 12-hour cycles) having phase shift on clock time, with interin-dividual variability on the 24-hour rhythm adjusted mean, the ampli-tudes of the cosine terms, phase shift, and clock time. Interoccasionvariability was also included on the 24-hour rhythm adjusted mean,the amplitude of the cosine term by 24-hour cycle and the clock time.The population standard of the 24-hour rhythm adjusted mean was95.6 mmHg [95% CI: 93.5–97.7] and its interindividual and interoc-casion variability were 9.2 CV% [6.2–12.1] and 3.2 CV% [0.6–5.7],respectively. The residual error was 7.48 mmHg.
CONCLUSIONS: A two-cosine model was able to characterizethe circadian rhythm of ABPM measured DBP in this patient popu-lation. This model can be used as the baseline model to characterizethe exposure-response relationship of antihypertensive agents.
CLINICAL PHARMACOLOGY & THERAPEUTICS2005;77(2) American Society for Clinical Pharmacology and Therapeutics P57