For CYP2D6, the PM incidence (8.0%) is in accordance with literature data. The CYP2C19, PM incidence (1.8%) is low compared to reports from other European countries. For mephenytoin, the acidification procedure has been shown to be very important for the confirmation of CYP2C19 PMs. In EM females compared to EM males, CYP2D6 activity is increased and CYP2C19 activity is reduced. For CYP2C19 in particular this reduction is substantial and most pronounced in the age range from 18 to 40 years. For CYP2C19, the reduced activity is associated with the use of oral contraceptives.
Telmisartan is a new angiotensin receptor antagonist possessing potent, selective, and insurmountable inhibitory activity specific to the angiotensin II type 1 (AT 1 ) receptor. The current study was performed to determine the inhibition of the angiotensin II pressor response by telmisartan in 48 healthy volunteers challenged with hypertension-inducing doses of i.v. angiotensin II. Subjects were challenged with this dose of angiotensin II at intervals between 0.25 and 48 h after double-blind single-dose oral administration of telmisartan 20 mg (n = 12), 40 mg (n = 12), or 80 mg (n = 12) or placebo (n = 12) in parallel groups. Diastolic and systolic blood pressure and pulse rate were recorded continuously using a servophotoplethysmograph. Urine samples were collected during the study for urinalysis. Tolerability of telmisartan, in comparison with placebo, was also monitored throughout the study. Telmisartan 20-80 mg dose dependently inhibited the increase in diastolic and systolic blood pressure induced by angiotensin II. Telmisartan 40 mg produced 80.1% maximum inhibition, and with 80 mg 89.6% maximum inhibition of diastolic blood pressure was achieved. Inhibition was apparent after 0.3-1.1 h and was still observed 48 h after administration for all telmisartan doses. The inhibitory effect of telmisartan 20, 40, and 80 mg, 48 h after dosing was significantly greater than that of placebo. A > 25% inhibition of the angiotensin II response on diastolic blood pressure was detected until 26.9, 35.4, and 40.5 h, respectively, after telmisartan 20 mg, 40 mg, and 80 mg. Anti-clockwise hysteresis was observed, indicating a delay and longer persistence of effect than to be expected from the plasma concentration-time course. The slow dissociation of telmisartan from the receptor probably contributed to this hysteresis. The incidence of adverse events was comparable in telmisartan-and placebo-treated subjects and was not dose dependent. In conclusion, telmisartan 40 mg provides rapid-onset, well-tolerated, and near-maximal inhibition of angiotensin II-induced hypertension, with maintenance of the inhibitory effect for 48 h.
A method for simultaneous phenotyping and genotyping for CYP2D6 and CYP2C19 was tested. Six healthy volunteers were selected (three extensive and three poor metabolisers for CYP2D6). CYP2D6 was probed with dextromethorphan and metoprolol and CYP2C19 was probed with omeprazole. Blood samples were collected and analysed for dextromethorphan, dextrorphan, metoprolol, alpha-hydroxymetoprol, omeprazole and 5-hydroxyomeprazole by HPLC. Genotyping was performed for both CYP2D6 and CYP2C19. Generally, plasma levels could be measured up to 8 h post-dose except for alpha-hydroxymetoprolol in poor metabolizers (PMs) and dextromethorphan in extensive metabolizers (EMs) (35% below quantification limit). The correlation between the metabolic ratio based on timed individual measurements and the metabolic ratio based on the AUC0-12 values was significant at 3 h post-dose for all probes. In conclusion, the following procedure is suggested: administer metoprolol (100 mg) and omeprazole (40 mg); after 3 h, take a blood sample to assess the genotype and the metabolic ratio for CYP2D6 (metoprolol over alpha-hydroxymetoprolol) and CYP2C19 (omeprazole over 5-hydroxyomeprazole) in plasma. With this procedure, all necessary information on the individual CYP2D6 and CYP2C19 metabolising capacity can be obtained in a practical, single-sample approach.
Aims To further evaluate mephenytoin as a probe for CYP2C19 phenotyping. Methods Healthy subjects (n=2638) were phenotyped using the urinary (S)-mephenytoin to (R)-mephenytoin ratio. This method was evaluated for (a) the stability of the S/R-ratio following sample storage, (b) the intraindividual reproducibility of the ratio, and (c) the occurrence of adverse events. Results After prolonged storage, the S/R-ratio of samples from extensive metabolisers (EM) increased up to 85%. In 1.5% of the cases (1 out 66), this led to incorrect classi®cation of phenotype. In EMs, but not in poor metabolisers (PMs), the S/Rratio increased after acid treatment. The intraindividual reproducibility of the mephenytoin phenotyping procedure was 28%. No major side-effects were observed and there was no relationship between the incidence of side-effects and the phenotype of the subject. Conclusions After prolonged storage the S/R-ratio signi®cantly increased in EMs and, although low, the risk of incorrect classi®cation should not be ignored. Our data support the use of mephenytoin as a safe drug for CYP2C19 phenotyping.
Patients with impaired CYP2D6 metabolism received fewer CYP2D6 drugs. PMs were more prone to Parkinsonian-like side effects as evidenced by more prescriptions for drugs combating these side effects. Dose titrations were not often used to compensate for genetic polymorphisms. Pharmacy records might be a useful tool to detect differences related to polymorphic metabolism.
Dopamine D2 receptor agonists represent a first line treatment option in young patients with signs and symptoms of idiopathic Parkinson's disease. An association between the use of D2 receptor agonists in Parkinson's disease patients and heart failure has been reported. The identification of the underlying mechanism is needed to minimize the resultant cardiovascular morbidity. In a phase I clinical trial, a D2 receptor agonist (pramipexole) was administered to 52 healthy male subjects following a dose escalation scheme. Serial measurements of resting blood pressure, heart rate, and derived parameters including pulse pressure, pulsatile stress, and rate pressure product were analysed. Statistically significant and clinically relevant increases in most of the assessed parameters were found. Ten subjects were removed prematurely from the trial because of clinically significant increases in blood pressure and/or heart rate requiring immediate intervention with IV rescue medications including a selective β-1 blocker. The observed drug-related changes in vital signs were of clinical relevance and might explain some of the cardiovascular morbidity reported in patients receiving D2 receptor agonist in clinical settings. We suggest that the additional use of a β-1 blocking agent might mitigate the risk of cardiovascular morbidity among patients receiving long-term D2 receptor agonists.
SUMMARYPurpose This retrospective follow-up study investigates whether cytochrome P450-2D6 (CYP2D6) genotype explains variability in plasma concentrations of psychotropic drugs in daily psychiatric practice. Methods The study population consisted of 62 hospitalised psychiatric patients genotyped for CYP2D6. Primary endpoint was the normalised plasma concentration ratio which was defined as the [measured concentration]/[mean therapeutic concentration] allowing comparison of plasma concentrations of different substrates. Secondary endpoint was a plasma concentration above the therapeutic range. The determinant was CYP2D6 genotype classified as ultrarapid metaboliser (UM), extensive metaboliser (EM), intermediate metaboliser (IM), or poor metaboliser (PM). The relation between CYP2D6 genotype and the normalised plasma concentration ratio was assessed with a linear mixed-effects model after adjustment for the Prescribed Daily Dose (PDD). The risk of having a plasma concentration above the therapeutic range was assessed with a logistic mixed-effects model. Results For antidepressants, CYP2D6 genotype PM (1.68 (95%CI: 1.01-2.28)) and IM (1.09 (95%CI: 0.77-1.29)) were associated with higher normalised plasma concentration ratios of antidepressants compared to ). In addition, the risk of a plasma concentration above the therapeutic range was increased for PMs (OR 33.1 (95%CI: 2.0-544.6)) and IMs (OR 8.2 (95%CI: 1.1-60.3)) relative to EMs using antidepressants. CYP2D6 genotype could not clearly explain variability in plasma concentrations of antipsychotics possibly due to a low frequency of therapeutic drug monitoring (TDM) in antipsychotics primarily metabolised by CYP2D6 in daily psychiatric practice. Conclusions CYP2D6 genotype contributes to clinically relevant variability in plasma concentrations of antidepressants but probably not antipsychotics in daily clinical practice.
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