Impact of quinidine on plasma and cerebrospinal fluid concentrations of codeine and morphine after codeine intake

Objective: The analgesic effect of codeine depends on its O-demethylation to morphine via sparteine oxygenase (CYP2D6) in the liver and presumably also via this enzyme in the CNS. We studied the ability of quinidine, which is a potent inhibitor of CYP2D6, to penetrate the blood brain barrier and its pssible impact on codeine O-demethylation in CNS. Methods: The study comprised 16 extensive and one poor metaboliser of sparteine, who underwent spinal anaesthesia for urinary tract surgery or examination. Eight patients were given an oral dose of 125 mg codeine and 9 patients (including the poor metaboliser) were given 200 mg quinidine 2 h before the same dose of codeine. Plasma and spinal fluid samples were collected 2 h after codeine intake. Results: Free concentrations of quinidine were 11-times lower in cerebrospinal fluid than in plasma, and ranged from 9–15 nmol·l^–1. Morphine concentrations were significantly lower in patients pre-treated with quinidine, both in plasma (median 1.45 nmol·l^–1, range 0.74–1.95 nmol·l^–1 vs 9.86 nmol·l^–1, range 4.59–28.4 nmol·l^–1) and in cerebrospinal fluid (0.23, 0.16–0.61 nmol·l^–1 vs 3.63, 0.6–8.09 nmol·l^–1). The morphine/codeine concentration ratio in plasma (3.07×10^–3, 1.68–3.68×10^–3 vs 19.87×10^–3, 9.87–66.22×10^–3) and in cerebrospinal fluid (0.83×10^–3, 0.58–1.45×10^–3 vs 7.19×10^–3, 2.03–17.7×10^–3) was also lower. The morphine/-codeine concentration ratios were significantly lower in cerebrospinal fluid both without and with quinidine, but the difference between the plasma and spinal fluid ratios was significantly smaller with quinidine than without (p=0.0002). Conclusion: Quinidine penetrates the blood brain barrier poorly, but quinidine pre-treatment leads to pronounced lowering of the cerebrospinal fluid concentration of morphine after codeine intake. However, the O-demethylation of codeine in CNS may not be totally blocked by quinidine.     

O-demethylation of codeine to morphine inhibited by low-dose levomepromazine

Purpose  Codeine/paracetamol (C/P) and levomepromazine (L) are frequently co-administered for the treatment of acute back pain, but the efficacy/effectiveness of this combination drug therapy has not been evaluated. The demethylation of codeine to morphine is catalyzed by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6), of which levomepromazine (methotrimeprazine) is a known inhibitor. The aim of this study was to investigate whether low-dose levomepromazine inhibits the formation of morphine from codeine in a patient population of homozygous extensive (EM) and heterozygous extensive (HEM) metabolizers of CYP2D6. Methods  Our patient cohort consisted of 29 patients hospitalized for acute back pain who were randomized to a 24-h treatment with either C/P (60 mg codeine + 1000 mg paracetamol) four times daily or to L+C/P (levomepromazine 5 + 5 + 5 + 10 mg + C/P) four times daily. After zero-urine sampling (baseline), the treatment was started and urine collected for 24 h. Blood samples were later genotyped for the CYP2D6*3, *4, and *6 polymorphisms by the PCR (LightCycler system) and for the *5 polymorphism using long PCR, to identify EM and HEM and to eliminate CYP2D6 poor metabolizers. Urine samples were analyzed using the CEDIA immunoassay and gas chromatography–mass spectrometry after enzymatic hydrolysis of glucuronide conjugates. O-demethylation ratios of codeine were calculated as hydrolyzed (total) concentrations of morphine/morphine + codeine. Results  Twenty-two of the patients fulfilled the inclusion criteria, of whom ten were EM (five C/P and five L+C/P) and twelve were HEM (six C/P and six L+C/P) for functional CYP2D6 alleles. In the EM group, the median O-demethylation ratio was significantly higher (P = 0.016, Mann–Whitney test) after the C/P treatment (0.092, range 0.041–0.096) than after the L+C/P treatment (0.031, range 0.009–0.042). However, there was no significant difference between these two treatments in either the HEM group [n = 12; 0.024 (range 0.011–0.042) vs. 0.026 (range 0.009–0.041), respectively; P = 1.00] or in the combined EM/HEM group [11 C/P + 11 L+C/P; 0.041 (range 0.011–0.096) vs. 0.030 (range 0.009–0.042), respectively; P = 0.122]. Conclusions  Our study revealed significant inhibition in the O-demethylation of codeine to morphine in homozygous EM of CYP2D6 treated with low-dose levomepromazine and codeine/paracetamol, compared to treatment with codeine/paracetamol only. No significant difference could be detected in HEM or in the mixed and heterogenous group of EM/HEM. In patients prescribed this drug combination, the amount of morphine generated by the O-demethylation of codeine may be insufficient for effective pain relief. The therapeutic effect of codeine in the treatment of acute back pain should be assessed with and without levomepromazine.     

Lack of effect of paracetamol on the pharmacokinetics and metabolism of codeine in man

Summary Plasma and urine concentrations of codeine and its measurable metabolites were determined by HPLC in six healthy subjects after a single 30 mg oral dose of codeine either alone or after 7 doses of 1 g paracetamol 8 hourly.After codeine alone, the t_1/2 (h), AUC (mol·l^–1·h) and CL_R (ml·min^–1) for codeine were 2.2, 0.81, and 252 respectively. These were not significantly altered by paracetamol: 2.2, 0.84, and 291 respectively.For codeine-6-glucuronide the values were 2.4, 22.0, and 29.7 respectively. These were not significantly different from those after codeine plus paracetamol: 2.4, 21.9, and 39.6. There were no significant differences between the two treatments in the apparent partial clearances (ml·min^–1) of codeine to morphine (88 codeine alone, 70 codeine plus paracetamol), to norcodeine (71 codeine alone, 88 codeine plus paracetamol), and to codeine-6-glucoronide (820 codeine alone, 1022 codeine plus paracetamol).The urinary excretion of codeine-6-glucuronide, morphine, norcodeine, and codeine were not significantly different between the two treatments.     

Lack of relationship between quinidine pharmacokinetics and the sparteine oxidation polymorphism

Quinidine is a very potent inhibitor of CYP2D6, but the role of the enzyme in the biotransformation of quinidine has only been investigated in a single in vitro study and in two small in vivo experiments, with contradictory results. The present investigation was designed to present definite evaluation of whether quinidine is metabolised by CYP2D6. Eight poor metabolizers (PM) and 8 extensive metabolizers (EM) of sparteine each took one oral dose of 200 mg quinidine. In the EM, the total clearance, the clearance via 3-hydroxylation and the clearance via N-oxidation, were 33, 3.7 and 0.23 l·h^–1, respectively. In the PM, the corresponding values were 29, 3.1 and 0.18 l·h^–1, respectively. There were no statistically significant differences between EM and PM in any of these pharmacokinetic parameters. It is concluded that CYP2D6 is not an important enzyme for the oxidation of quinidine.     

In vitro study on the effect of peucedanol on the activity of cytochrome P450 enzymes

ContextPeucedanol is a major extract of Peucedanum japonicum Thunb. (Apiaceae) roots, which is a commonly used herb in paediatrics. Its interaction with cytochrome P450 enzymes (CYP450s) would lead to adverse effects or even failure of therapy.ObjectiveThe interaction between peucedanol and CYP450s was investigated.Materials and methodsPeucedanol (0, 2.5, 5, 10, 25, 50, and 100 μM) was incubated with eight human liver CYP isoforms (CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1), in pooled human liver microsomes (HLMs) for 30 min with specific inhibitors as positive controls and untreated HLMs as negative controls. The enzyme kinetics and time-dependent study (0, 5, 10, 15, and 30 min) were performed to obtain corresponding parameters in vitro.ResultsPeucedanol significantly inhibited the activity of CYP1A2, 2D6, and 3A4 in a dose-dependent manner with IC₅₀ values of 6.03, 13.57, and 7.58 μM, respectively. Peucedanol served as a non-competitive inhibitor of CYP3A4 with a K_i value of 4.07 μM and a competitive inhibitor of CYP1A2 and 2D6 with a K_i values of 3.39 and 6.77 μM, respectively. Moreover, the inhibition of CYP3A4 was time-dependent with the K_i/K_inact value of 5.44/0.046 min/μM.Discussion and conclusionsIn vitro inhibitory effect of peucedanol on the activity of CYP1A2, 2A6, and 3A4 was reported in this study. As these CYPs are involved in the metabolism of various drugs, these results implied potential drug-drug interactions between peucedanol and drugs metabolized by CYP1A2, 2D6, and 3A4, which needs further in vivo validation.     

Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol

Objective: This study was designed to investigate whether the in vivo metabolism of tramadol was influenced by CYP2D6 polymorphism. Methods: The extent of tramadol O- and N-demethylation was calculated by determining the amounts of tramadol and O- and N-desmethyltramadol in 24 h urine after ingestion of a test dose of tramadol. The O- and N-demethylation rates were calculated by dividing the 24-h urinary excretion amount of tramadol by that of O-and N-desmethyltramadol. Volunteers were phenotyped for CYP2D6 polymorphism using sparteine as an in vivo probe. Results and conclusion: High correlation was found between tramadol-O-demethylation and sparteine oxidation in 71 extensive metabolizers of sparteine (r _s= 0.544). The mean metabolic ratio of tramadol O-demethylation was significantly higher in poor metabolizers of sparteine than in extensive metabolizers (4.4 vs 0.8). These in vivo results confirm that tramadol O-demethylation is carried out to a large extent by the polymorphic CYP2D6. Received: 9 January 1997 / Accepted in revised form: 23 July 1997     

The effect of cimetidine or omeprazole on the pharmacokinetics of escitalopram in healthy subjects

AIMS: To investigate the effects of co-administration of cimetidine or omeprazole on the pharmacokinetics of escitalopram. METHODS: Two randomized placebo-controlled crossover studies were carried out. Sixteen healthy subjects were administered placebo, or cimetidine (400 mg twice daily) for 5 days (study 1) or omeprazole (30 mg once daily) for 6 days (study 2). On day 4 (study 1) or day 5 (study 2), a single dose of escitalopram (20 mg) was administered. Blood samples were taken at predetermined times for the measurement of serum concentrations of escitalopram and its demethylated metabolite (S-DCT). Treatment-emergent adverse events were also monitored. RESULTS: Co-administration with cimetidine caused a moderate increase in the systemic exposure [AUC0, infinity] to escitalopram (geometric mean ratio = 1.72, [95% CI 1.34, 2.21]) and a small increase in t(1/2) from 23.7 to 29.0 h (5.24 h [3.75, 6.70]). Co-administration with omeprazole also resulted in a moderate increase in the escitalopram AUC(0, infinity) (1.51 [1.39, 1.64]) and a small increase in t(1/2) from 26.5 to 34.8 h (8.3 h [6.44, 10.2]). There was no significant change in S-DCT AUC0, infinity after co-administration of either cimetidine or omeprazole. Co-administration of cimetidine or omeprazole had no effect on the incidence of treatment-emergent adverse events. CONCLUSIONS: In view of the good tolerability of escitalopram, the pharmacokinetic changes observed on co-administration with cimetidine or omeprazole are unlikely to be of clinical concern.     

Effect of cimetidine on quinidine bioavailability

Elevations in quinidine steady-state serum concentrations have been reported in patients who received cimetidine concurrently. Studies in normal volunteers have shown that areas under the serum concentration-time curve of orally administered quinidine are higher when quinidine is given during chronic cimetidine therapy as compared to under control conditions. The mechanism for this interaction is generally ascribed to decreased hepatic clearance as a consequence of enzyme inhibition. In this study, we show that cimetidine also decreases the bioavailable fraction of quinidine.     

The effect of paroxetine on the pharmacokinetics,safety, and tolerability of ramosetron in healthy subjects

Objective The aim of our study was to investigate the effects of multiple doses of paroxetine on the pharmacokinetics, safety, and tolerability of a single oral 10-μg dose of ramosetron. Methods This was an open, one-sequence crossover design study. On day 1, healthy male and female subjects were administered a single dose of 10 μg ramosetron. On the morning of day 3, the subjects were administered paroxetine to reach steady state, which consisted of morning doses of 20 mg on days 3–12. The dose on day 11 was administered in combination with a single dose of 10 μg ramosetron. Results In subjects genotyped as extensive CYP2D6 metabolizers, coadministration of paroxetine with ramosetron resulted in an increase in area under the curve from 0 to infinity (AUC_0-inf) and the peak concentration (C_max) of ramosetron by 1.14-fold (90% confidence interval (CI): 1.07–1.22) and by 1.06-fold (90% CI: 1.00–1.11), respectively. Conclusions It can be concluded that the single-dose pharmacokinetic profile of ramosetron 10 μg is not affected to a clinically relevant degree by paroxetine 20 mg once daily administered for 10 days.     

The effect of resveratrol on pharmacokinetics of aripiprazole in vivo and in vitro

1.?The objective of this study were to investigate the effect of orally administered resveratrol on the pharmacokinetics of aripiprazole (APZ) in rat, and the inhibitory effects of resveratrol on APZ dehydrogenation activity in liver microsomes and human cytochrome P450 3A4 and 2D6.

2.?Twenty-five healthy male Sprague–Dawley rats were randomly divided into five groups: A (control group), B (multiple dose of 200?mg/kg resveratrol), C (multiple dose of 100?mg/kg resveratrol), D (a single dose of 200?mg/kg resveratrol) and E (a single dose of 100?mg/kg resveratrol). A single dose of 3?mg/kg APZ administered orally 30?min after administration of resveratrol. In addition, CYP2D6*1, CYP3A4*1, human and rat liver microsomes were performed to determine the effect of resveratrol on the metabolism of APZ in vitro.

3.?The multiple dose of 200 or 100?mg/kg resveratrol significantly increased the AUC and C_max of APZ. The resveratrol also obviously decreased the CL, but without any significant difference on t_1/2 in vivo. On the other hand, resveratrol showed inhibitory effect on CYP3A4*1, CYP2D6*1, human and rat microsomes, the IC₅₀ of resveratrol was 6.771, 87.87, 45.11 and 35.59?μmol?l^?1, respectively.

4.?Those results indicated more attention should be paid when APZ was administrated combined with resveratrol.     

Effect of ketoconazole on the pharmacokinetics of imipramine and desipramine in healthy subjects

Aims The aim of the study was to characterize further the role of CYP3A4 in the metabolism of tricyclic antidepressants.
Methods The effect of oral ketoconazole (200  mg day⁻¹ for 14 days) on the kinetics of a single oral dose of imipramine (100  mg) and desipramine (100  mg) was evaluated in two groups of six healthy male subjects.
Results Ketoconazole administration was associated with a decrease in imipramine apparent oral clearance (from 1.16±0.21 to 0.96±0.20  l h⁻¹  kg⁻¹, mean±s.d.; ' of2\P<0.02), a prolongation in imipramine half-life (from 16.7±3.3 to 19.2±5.4  h, ' of2\P<0.05) and a decrease in area under the curve of metabolically derived desipramine (from 3507±1707 to 3180±1505  nmol  l⁻¹  h, P <0.05), whereas concentrations of 2-hydroxy-imipramine were unaffected. In the subjects given desipramine, no significant changes in desipramine and 2-hydroxy-desipramine kinetics were observed during ketoconazole treatment.
Conclusions These findings indicate that ketoconazole, a relatively specific inhibitor of CYP3A4, inhibits the N -demethylation of imipramine without affecting the 2-hydroxylation of imipramine and desipramine. This interaction, confirms that CYP3A4 plays a role in the demethylation of tricyclic antidepressants.     

The effect of perazine on the CYP2D6 and CYP2C19 phenotypes as measured by the dextromethorphan and mephenytoin tests in psychiatric patients

There is evidence that the antipsychotic drug perazine is an inhibitor of CYP2D6. This study aimed at evaluating its effect on CYP2D6 and CYP2C19 activities in submitting psychiatric patients to phenotyping with dextromethorphan and mephenytoin, respectively, substrates of these enzymes, before and during a treatment with perazine. A total of 31 patients were phenotyped with dextromethorphan (CYP2D6) and mephenytoin (CYP2C19) before and after a 2‐week treatment with 450 ± 51 mg/day (mean ± sd) perazine. At baseline, five patients appeared to be poor metabolizers (PM) of dextromethorphan and two patients of mephenytoin. The metabolic ratio (MR) of dextromethorphan/dextrorphan as determined in collected urine increased significantly (Wilcoxon; P < .0001) from baseline (0.39 ± 1.38 [mean ± sd]) till day 14 (1.46 ± 2.22). In 19 out of 26 extensive metabolizers (EM) of dextromethorphan, the phenotype changed from EM to PM. This suggests an almost complete inhibition of CYP2D6 by perazine and/or its metabolites. On the other hand, perazine (or some of its metabolites) did seemingly not inhibit CYP2C19. In conclusion, this study suggests that in patients treated with perazine and co‐medicated with CYP2D6 substrates, there could be an increased risk of adverse effects as a consequence of a pharmacokinetic interaction.     

The effect of carbamazepine on the 2-hydroxylation of desipramine

The effect of carbamazepine (CBZ, 200 mg twice daily for 28 days) on the kinetics of a single oral dose of desipramine (DMI, 100 mg) was investigated in six healthy volunteers. Compared with a control session, treatment with CBZ caused a marked increase in DMI apparent oral clearance (from 1.05 ± 0.40 to 1.38 ± 0.52 1 h per kg, means ± SD,P<0.01) and a significant shortening in DMI half-life (from 22.1 ± 3.5 to 17.8 ± 3.5 h,P<0.01). The amount of 2-hydroxy-desipramine (2-OH-DMI) excreted in urine over a 24-h period was significantly increased during CBZ intake (from 75 ± 15 to 92 ± 16 µmol,P<0.01). These findings suggest that CBZ induces the 2-hydroxylation of DMI, a reaction primarily catalyzed by the polymorphic CYP2D6 isozyme. This interaction may have considerable practical significance.     

In vitro inhibitory effects of dihydromyricetin on human liver cytochrome P450 enzymes

Context: Dihydromyricetin (DHM) is the most abundant and active flavonoid component isolated from Ampelopsis grossedentata (Hand-Mazz) W.T. Wang (Vitaceae) and it possesses numerous pharmacological activities. However, whether DHM affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear.

Materials and methods: The inhibitory effects of DHM on eight human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8) were investigated in vitro using human liver microsomes (HLMs).

Results: The results showed that DHM could inhibit the activity of CYP3A4, CYP2E1 and CYP2D6, with IC₅₀ values of 14.75, 25.74 and 22.69?μM, respectively, but that other CYP isoforms were not affected. Enzyme kinetic studies showed that DHM was not only a non-competitive inhibitor of CYP3A4 but also a competitive inhibitor of CYP2E1 and CYP2D6, with Ki values of 6.06, 9.24 and 10.52?μM, respectively. In addition, DHM is a time-dependent inhibitor for CYP3A4 with K_I/K_inact value of 12.17/0.057?min^?1?μM^?1.

Discussion and conclusion: The in vitro studies of DHM with CYP isoforms indicate that DHM has the potential to cause pharmacokinetic drug interactions with other co-administered drugs metabolized by CYP3A4, CYP2E1 and CYP2D6. Further clinical studies are needed to evaluate the significance of this interaction.     

Effect of a traditional Chinese medicine Liu Wei Di Huang Wan on the activities of CYP2C19, CYP2D6 and CYP3A4 in healthy volunteers

1. Liu Wei Di Huang Wan (LDW), a well-known traditional Chinese medicine, is widely used for the treatment of various diseases in China. This study was designed to investigate the potential herb–drug interactions of LDW in healthy volunteers and attempted to ascertain whether the interaction might be affected by genotypes.

2. We assessed the effect of LDW on the activities of CYP2C19, CYP2D6 and CYP3A4 in 12 Chinese healthy subjects in a single-center, controlled, non-blinded, two-way crossover clinical trial. The subject pool consisted of six extensive metabolizers with CYP2C19*1/*1 and six poor metabolizers with CYP2C19*2/*2. Placebo or 4.8?g LDW (12 pills, 0.2?g/pill, twice daily) was given to each participant for 14 continuous days with a wash-out period of 2 weeks after an oral administration of 30?mg omeprazole, 30?mg dextromethorphan hydrobromide and 7.5?mg midazolam. The activities of CYP2C19, CYP2D6 and CYP3A4 were ascertained by their respective plasma or urinary metabolic ratios on day 14 post-treatment.

3. There is no difference in the activities of the three tested enzymes before or after a 14-day administration of LDW. LDW had no effect on the pharmacokinetic parameters of the substrates and their metabolites.

4. A 14-day administration of LDW did not affect the activities of CYP2C19, CYP2D6 and CYP3A4. LDW is unlikely to cause pharmacokinetic interaction when it is combined with other medications predominantly metabolized by these enzymes.

     

中国汉族、维吾尔族、哈萨克族人群中可溶性细胞黏附分子的表达与CYP2D6基因多态性

目的:探讨可溶性细胞黏附分子-1在汉族、维吾尔族、哈萨克族正常人血清中的表达水平是否存在民族间差异以及与CYP2D6基因多态性是否有关。方法:ELISA双抗体夹心法。结果:血清中可溶性细胞黏附分子-1含量:汉族为35~1 086μg.L-1,维吾尔族为40~1 024μg.L-1,哈萨克族为45~975μg.L-1。结论:可溶性细胞黏附分子-1的含量在汉族与维吾尔族、汉族与哈萨克族、维吾尔族与哈萨克族之间差异均无显著性。     

The postoperative pharmacokinetics of codeine

Summary The metabolism and systemic availability of codeine have been studied in 12 patients after cholecystectomy. They were given 20 mg codeine as an IV bolus dose on the first day after surgery and 50 mg codeine as a single oral on the fourth day after surgery. Codeine had a medium to high extraction ratio and a total plasma clearance of 10.8 (4.3) ml·min^–1·kg^–1. The clearance varied fourfold between subjects. All the patients were extensive metabolizers with regard to the debrisoquine/sparteine polymorphism, as tested using dextromethorphan as the probe drug. Nevertheless, the formation of morphine from codeine was very small and plasma morphine concentrations were below the detection limit of 3.3 nmol·1^–1 (1 ng·ml^–1). As a corollary, the morphine/codeine ratio in the the concentration-time curves was less than 3% in all the patients.The systemic availability of codeine varied extensively between subjects (range 12–84%). This might partly explain differences in the dose of codeine required as an analgesic.     

Screening of drug metabolizing enzymes for fusidic acid and its interactions with isoform-selective substrates in vitro

1.?Fusidic acid (FA) is widely used for the treatment of infections of sensitive osteomyelitis or skin and soft tissue caused by bacteria. However, the role of cytochrome P450s (CYPs) in the metabolism of FA is unclear. In the present study, we screened the main CYPs for the metabolism of FA and studied its interactions with isoform-selective substrates in vitro.

2.?The main CYP450s were screened according to the inhibitory effect of specific inhibitors on the metabolism of FA in human liver microsomes (HLMs) or recombinant CYP isoforms. Enzyme kinetic parameters including K_i, K_i′, V_max, and IC₅₀ were calculated to determine the potential of FA to affect CYP-mediated metabolism of isoform-selective substrates.

3.?FA metabolism rate was inhibited by 49.8% and 83.1% under CYP2D6, CYP3A4 selective inhibitors in HLMs. In recombinant experiment, the inhibitory effects on FA metabolism were 83.3% for CYP2D6 and 58.9% for CYP3A4, respectively. FA showed inhibition on CYP2D6 and CYP3A4 with K_is of 13.9 and 38.6?μM, respectively. Other CYP isoforms including CYP1A2, CYP2A6, CYP2C9, CYP2E1, and CYP2C19 showed minimal or no effect on the metabolism of FA.

4.?FA was primarily metabolized by CYP2D6 and CYP3A4 and showed a noncompetitive inhibition on CYP2D6 and a mixed competitive inhibition on CYP3A4. Drug–drug interactions between FA and other chemicals, especially with substrates of CYP2D6 and CYP3A4, are phenomena that clinicians need to be aware of and cautious about.     

Atomoxetine pharmacokinetics in healthy Chinese subjects and effect of the CYP2D6*10 allele

AIMS: To characterize atomoxetine pharmacokinetics, explore the effect of the homozygous CYP2D6*10 genotype on atomoxetine pharmacokinetics and evaluate the tolerability of atomoxetine, in healthy Chinese subjects. METHODS: Twenty-four subjects, all CYP2D6 extensive metabolizers (EM), were randomized to receive atomoxetine (40 mg qd for 3 days, then 80 mg qd for 7 days) or matching placebo (2 : 1 ratio) in a double-blind fashion. Atomoxetine serum concentrations were measured following single (40 mg) and multiple (80 mg) doses. Adverse events, clinical safety laboratory data and vital signs were assessed during the study. RESULTS: Atomoxetine was rapidly absorbed with median time to maximum serum concentrations of approximately 1.5 h after single and multiple doses. Atomoxetine concentrations appeared to decrease monoexponentially with a mean apparent terminal half-life (t(1/2)) of approximately 4 h. The apparent clearance, apparent volume of distribution and t(1/2) following single and multiple doses were similar, suggesting linear pharmacokinetics with respect to time. Homozygous CYP2D6*10 subjects had 50% lower clearances compared with other EM subjects, resulting in twofold higher mean exposures. No clinically significant changes or abnormalities were noted in laboratory data and vital signs. CONCLUSIONS: The pharmacokinetics of atomoxetine in healthy Chinese subjects appears comparable to other ethnic populations. Multiple dosing of 80 mg qd atomoxetine was well tolerated in this study.     

Effect of quinidine on the intestinal secretion of digoxin in guinea pigs

Following i.v. injection of digoxin (10 μg kg^?1) the ratio between digoxin concentrations in the lumen of jejunal loops perfused in situ and in plasma (L/P) of guinea pigs increased linearily with time. After 3 h, L/P was 8·7, indicating net secretion of digoxin against a concentration gradient. In quinidine treated animals (100 mg kg^?1 p.o., 2h before experiment) both the L/P ratio (5·7; p < 0·01) and the digoxin content of jejunal tissue (– 32 per cent; p < 0·01) were markedly reduced. It is suggested that quinidine reduces the extrarenal clearance of digoxin at least in part by inhibiting the intestinal secretion of this glycoside.