Pharmacokinetic consequences of CYP2D6 genotypes with emphasis on gene duplication/amplification
Author: Dalén, Per
Date: 2000-01-28
Location: Föreläsningssalen R74, Rehabgatan, plan 6, Huddinge sjukhus
Time: 9.00
Department: Institutionen för medicinsk laboratorievetenskap och teknik / Department of Laboratory Sciences and Technology
Abstract
The relationship between the major Caucasian and Oriental CYP2D6
genotypes and the disposition of two CYP2D6 substrates nortriptyline and
debrisoquine was investigated.
Caucasians with 0, 1, 2, 3/4 and 13 functional CYP2D6-genes as well as
Chinese and Korean subjects homo- and heterozygous for the CYP2D6*1 and
CYP2D6*10 alleles were included. Single oral doses of 25 mg nortriptyline
were given to all subjects except for ultrarapid metabolisers who were
given a 50 mg dose to ensure accurate measurements of drug
concentrations. Except for the Chinese all subjects also were given a
single oral dose of 20 mg debrisoquine at a separate occasion. A very
clear relationship between the number of functional CYP2D6 genes and the
clearance of nortriptyline and debrisoquine and their metabolites was
shown in Caucasians. The 0-96 hr mean overall urinary recovery of
debrisoquine and its metabolites decreased with increasing number of
functional genes. Renal clearance of debrisoquine decreased with the time
after dose intake and also with the increasing number of functional
genes. Significant differences in the kinetics of nortriptyline were
shown between Chinese homozygous for CYP2D6*10 and those heterozygous or
homozygous for the functional wildtype allele (*1). Koreans heterozygous
for the CYP2D6*1 and *10 genes were shown to have similar capacity to
metabolise debrisoquine and nortriptyline as compared to individuals
homozygous for the CYP2D6*1 gene among both Koreans and Caucasians. When
present in only one copy in the CYP2D6 locus, the CYP2D6*10 allele only
has a marginal decreasing effect on the CYP2D6 enzyme activity. However,
when present in two copies the decreasing effect on the enzyme is more
pronounced. Five Caucasians with three or more functional CYP2D6 genes
and a metabolic ratio (MR) of debrisoquine < 0. 15 received single oral
doses of 5, 10, 20, 40, 80 and 160 mg quinidine. Four hours after the
quinidine dose, 10 mg oral debrisoquine was given, urine was collected
for 6 hours and debrisoquine MRs were calculated. A dose-effect
relationship could be established for quinidine with regard to the
inhibitory effect on CYP2D6 activity. To reach an MR of 1-2, subjects
with 3 or 4 functional genes required a quinidine dose of about 40 mg,
while subjects with 13 functional genes required about 80 mg of
quinidine.
We conclude that the number of functional CYP2D6 genes, and especially
the presence of multiple functional CYP2D6-genes is of quantitative
importance for the pharmacokinetics of drugs, whose metabolism is to a
major extent catalysed by CYP2D6. Ultrarapid metabolisers may develop low
plasma concentrations and show poor response or "therapy resistance" due
to inadequate drug plasma concentrations despite normal or high doses of
the drug assuming the parent compound is active. Such patients may also
produce large amounts of metabolite(s), which, in case they are
pharmacologically active, may contribute to the clinical effects of the
parent compound. Metabolites may also produce toxicological effects or
undesirable side-effects. The CYP2D6*10 allele in Orientals is associated
with higher plasma levels of nortriptyline compared with the CYP2D6*1
allele due to an impaired metabolism. However, heterozygosity for
CYP2D6*10 gene seems to decrease the CYP2D6-dependent elimination of
nortriptyline and debrisoquine to only a limited degree. Further studies
in Oriental subjects homozygous for CYP2D6*10 allele are required to
fully elucidate the pharmacokinetic consequences of the CYP2D6 genotype
in Orientals.
The utilisation of drugs may be improved and made more rational by using
both therapeutic drug monitoring, pheno- and genotyping tests to
establish individualised dosage strategies. Further prospective clinical
studies of adverse drug reactions, drug toxicity and therapeutic failure
in clinical evaluation of the consequences of different
genotypes/phenotypes are required to improve such an adjustment of drug
doses to the individual metabolic capacity.
List of papers:
I. Dalén P, Dahl ML, Ruiz ML, Nordin J, Bertilsson L (1998). "10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes" Clin Pharmacol Ther 63(4): 444-452
Pubmed
II. Yue QY, Zhong ZH, Tybring G, Dalén P, Dahl ML, Bertilsson L, Sjoqvist F (1998). "Pharmacokinetics of nortriptyline and its 10-hydroxy metabolite in Chinese subjects of different CYP2D6 genotypes" Clin Pharmacol Ther 64(4): 384-90
Pubmed
III. Dalén P, Dahl ML, Eichelbaum M, Bertilsson L, Wilkinson GR (1999). "Disposition of debrisoquine in Caucasians with different CYP2D6-genotypes including those with multiple CYP2D6-genes" Pharmacogenetics 9: 697-706
IV. Dalén P, Dahl ML, Bertilsson L (1999). "Inhibition of debrisoquine hydroxylation with quinidine in subjects with three or more functional CYP2D6-genes" Br J Clin Pharmacol (In Print)
V. Dalén P, Dahl ML, Roh, HK, Eichelbaum M, Wilkinsson G, Bertilsson L (1999). "A comparision of the disposition of debrisoquine and nortriptyline in Swedish and Korean subjects whith different CYP2D6 genotypes" Clin Pharmacol Ther (Submitted)
I. Dalén P, Dahl ML, Ruiz ML, Nordin J, Bertilsson L (1998). "10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes" Clin Pharmacol Ther 63(4): 444-452
Pubmed
II. Yue QY, Zhong ZH, Tybring G, Dalén P, Dahl ML, Bertilsson L, Sjoqvist F (1998). "Pharmacokinetics of nortriptyline and its 10-hydroxy metabolite in Chinese subjects of different CYP2D6 genotypes" Clin Pharmacol Ther 64(4): 384-90
Pubmed
III. Dalén P, Dahl ML, Eichelbaum M, Bertilsson L, Wilkinson GR (1999). "Disposition of debrisoquine in Caucasians with different CYP2D6-genotypes including those with multiple CYP2D6-genes" Pharmacogenetics 9: 697-706
IV. Dalén P, Dahl ML, Bertilsson L (1999). "Inhibition of debrisoquine hydroxylation with quinidine in subjects with three or more functional CYP2D6-genes" Br J Clin Pharmacol (In Print)
V. Dalén P, Dahl ML, Roh, HK, Eichelbaum M, Wilkinsson G, Bertilsson L (1999). "A comparision of the disposition of debrisoquine and nortriptyline in Swedish and Korean subjects whith different CYP2D6 genotypes" Clin Pharmacol Ther (Submitted)
Issue date: 2000-01-07
Publication year: 2000
ISBN: 91-628-3910-1
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