PMID- 11145052
OWN - NLM
STAT- MEDLINE
DCOM- 20010301
LR  - 20221207
IS  - 1387-2273 (Print)
IS  - 1387-2273 (Linking)
VI  - 749
IP  - 2
DP  - 2000 Dec 1
TI  - Enantioselectivity of debrisoquine 4-hydroxylation in Brazilian Caucasian 
      hypertensive patients phenotyped as extensive metabolizers.
PG  - 153-61
AB  - Debrisoquine (D), an antihypertensive drug metabolized to 4-hydroxydebrisoquine 
      (4-OHD) by CYP2D6, is commonly used as an in vivo probe of CYP2D6 activity and 
      can be used to phenotype individuals as either extensive (EMs) or poor 
      metabolizers (PMs) of such drugs as beta-adrenergic blockers, tricyclic 
      antidepressants, and class 1C antiarrhythmics. This report describes 
      reversed-phase HPLC systems by which D and 4-OHD or S-(+) and R-(-)-4-OHD in 
      urine are more selectively quantified without the need for derivatization 
      techniques. We also studied the urinary excretion of R-(-)- and 
      S-(+)-4-hydroxydebrisoquine in EM hypertensive patients in order to determine 
      weather 4-OHD formation exhibits enantioselectivity. Twelve patients with mild to 
      severe essential hypertension were admitted to the study. They received a single 
      tablet of Declinax containing 10 mg debrisoquine sulfate. All the urine excreted 
      during the following 8 h was collected. The debrisoquine metabolic ratio (DMR) 
      was calculated as % of dose excreted as D/% of dose excreted as 4-OHD and the 
      debrisoquine recovery ratio (DRR) was calculated as % of dose excreted as 4-OHD/% 
      of dose excreted as D+4-OHD. Debrisoquine and its metabolite were determined in 
      urine by HPLC using a reversed-phase Select B LiChrospher column, a mobile phase 
      of 0.25 N acetate buffer, pH 5-acetonitrile (9:1, v/v) and a fluorescence 
      detector. The limit of quantitation was determined to be 25.0 ng/ml for D and 
      18.75 ng/ml for 4-OHD. Intra- and inter-day relative standard deviations (RSDs) 
      were less than 10%. All hypertensive patients studied showed a DMR of less than 
      12.6 or a DRR higher than 0.12 and were classified as EMs. Direct 
      enantioselective separation on chiral stationary phase involved resolution of 
      S-(+)-4-OHD and R-(-)-4-OHD on a Chiralcel OD-R column with a mobile phase of 
      0.125 N sodium perchlorate, pH 5-acetonitrile-methanol (85:12:3, v/v/v). The 
      quantitation limit of each enantiomer was 3.75 ng/ml of urine. Intra- and 
      inter-day RSDs were less than 10% for each enantiomer. A high degree of 
      enantioselectivity in the 4-hydroxylation of D favouring the S-(+) enantiomer was 
      observed, resulting in R-(-)-4-OHD not detected in the urine of the EM 
      hypertensive patients studied.
FAU - Cerqueira, P M
AU  - Cerqueira PM
AD  - Universidade de Sao Paulo, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, 
      Departamento de Analises Clinicas, Toxicologicas e Bromatologicas, Brazil.
FAU - Mateus, F H
AU  - Mateus FH
FAU - Cesarino, E J
AU  - Cesarino EJ
FAU - Bonato, P S
AU  - Bonato PS
FAU - Lanchote, V L
AU  - Lanchote VL
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PL  - Netherlands
TA  - J Chromatogr B Biomed Sci Appl
JT  - Journal of chromatography. B, Biomedical sciences and applications
JID - 9714109
RN  - 0 (Antihypertensive Agents)
RN  - 59333-79-8 (4-hydroxydebrisoquin)
RN  - X31CDK040E (Debrisoquin)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antihypertensive Agents/metabolism/therapeutic use/*urine
MH  - Brazil
MH  - Calibration
MH  - *Chromatography, High Pressure Liquid/methods
MH  - Debrisoquin/analogs & derivatives/metabolism/therapeutic use/*urine
MH  - Female
MH  - Humans
MH  - Hypertension/drug therapy/ethnology/*urine
MH  - Male
MH  - Middle Aged
MH  - Molecular Conformation
MH  - Phenotype
MH  - Reproducibility of Results
MH  - White People
EDAT- 2001/01/06 11:00
MHDA- 2001/03/07 10:01
CRDT- 2001/01/06 11:00
PHST- 2001/01/06 11:00 [pubmed]
PHST- 2001/03/07 10:01 [medline]
PHST- 2001/01/06 11:00 [entrez]
AID - 10.1016/s0378-4347(00)00402-3 [doi]
PST - ppublish
SO  - J Chromatogr B Biomed Sci Appl. 2000 Dec 1;749(2):153-61. doi: 
      10.1016/s0378-4347(00)00402-3.