Ulrike Werner

Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment.

The beta1 selective beta-blocker metoprolol is metabolized predominantly but not exclusively by CYP2D6. Due to the polymorphism of the CYP2D6 gene, CYP2D6 activity varies markedly between individuals. Consequently, after short-term administration metoprolol plasma concentrations were found to be several fold higher in poor metabolizers than in extensive metabolizers. However, it is currently not known, whether the impact of the CYP2D6 polymorphism persists during long-term therapy, since alternate mechanisms of elimination or metabolism could be effective in this setting. The study comprised 91 Caucasian patients on long-term treatment with metoprolol (median duration of treatment 12.6 months; median daily drug dose: 47.5 mg/day). Metoprolol and alpha-OH-metoprolol plasma concentrations were assessed by HPLC. Genotyping detected the null alleles (*0): *3, *4, *5, *6, *7, *8, *12, *14, *15, the alleles *9, *10 and *41 associated with reduced enzymatic activity as well as the fully functional alleles *1 and *2. Genotype and allele frequencies were in accordance with published frequencies for the German population. The plasma metabolic ratio of metoprolol/alpha-OH-metoprolol was markedly affected by the genotype (P < 0.0001). In accordance, median adjusted metoprolol plasma concentrations were 6.2- and 3.9-fold higher in patients with *0/*0 genotypes (n = 8) and intermediate genotypes (n = 10), respectively, as compared to those with two fully functional alleles (n = 31; P < 0.01). In summary, the pronounced effect of the CYP2D6 genotype persists during long-term therapy, affecting both metabolic ratio and metoprolol plasma concentration.

Impact of the CYP2D6 Genotype on the Clinical Effects of Metoprolol: A Prospective Longitudinal Study

After administration of metoprolol, plasma concentrations of the drug are markedly higher in CYP2D6 poor metabolizers (PMs) than in non‐PMs. In a prospective double‐blind 3‐month study, we investigated whether this translates into differences in metoprolols effects after initiation of therapy. Despite administering equal doses to PMs and non‐PMs, metoprolol plasma concentrations were 4.9‐fold higher in the PM group. Metoprolol evoked significantly and persistently greater reductions in heart rate, diastolic blood pressure, and mean arterial pressure in PMs than in non‐PMs. It appears, therefore, that the CYP2D6 genotype contributes to interindividual differences in metoprolol response.

Celecoxib inhibits metabolism of cytochrome P450 2D6 substrate metoprolol in humans

In vitro data have shown that celecoxib inhibits the metabolism of cytochrome P450 (CYP) 2D6 substrates. However, very limited data are available on the influence of cyclooxygenase 2 inhibitors on the disposition of CYP2D6 substrates in humans. Therefore the objective of this study was to examine the effect of celecoxib and rofecoxib on the pharmacokinetics of the clinically relevant CYP2D6 substrate metoprolol.

Characterization of β-adrenoceptor antagonists as substrates and inhibitors of the drug transporter P-glycoprotein1

Transporter proteins such as P‐glycoprotein are major determinants of intracellular drug concentrations. Moreover, inhibition or induction of transporters is an important mechanism underlying drug interactions in humans. However, very little is known whether β‐adrenoceptor antagonists are substrates and/or inhibitors of P‐glycoprotein. Therefore, we investigated the P‐glycoprotein‐mediated transport of propranolol, metoprolol, bisoprolol, carvedilol and sotalol in P‐glycoprotein‐expressing Caco‐2 monolayers and inhibition of P‐glycoprotein‐mediated digoxin transport by the β‐adrenoceptor antagonists. A significant inhibition of polarized, basal to apical drug transport by the P‐glycoprotein inhibitor PSC‐833 was observed for bisoprolol (0.5 and 5 μm) and carvedilol (0.5 μm). Moreover, propranolol and carvedilol inhibited P‐glycoprotein‐mediated digoxin transport with IC50 values of 24.8 and 0.16 μm, respectively, whereas metoprolol and sotalol had no effect. Bisoprolol significantly inhibited directional digoxin transport at 50 and 250 μm by 31% and 44%, respectively. Taken together, P‐glycoprotein is likely to be one determinant of bisoprolol and carvedilol disposition in humans. In addition, the β‐adrenoceptor antagonists propranolol and carvedilol significantly inhibit P‐glycoprotein function thereby possibly contributing to drug interactions in humans (e.g. digoxin–carvedilol and cyclosporine–carvedilol).

Caffeine Accelerates Absorption and Enhances the Analgesic Effect of Acetaminophen

The aim of this study was to determine the analgesic effect of acetaminophen compared to a combination of both caffeine and acetaminophen or caffeine alone using tonic and phasic pain stimulation. Twenty‐four subjects were treated orally with 1000 mg acetaminophen, 130 mg caffeine, and a combination of both in a 4‐way crossover, double‐blind, placebo‐controlled study. Pharmacokinetics and analgesic effects were assessed by means of an experimental pain model based on pain‐related cortical potentials after phasic stimulation of the nasal mucosa with CO2 and based on pain ratings after tonic stimulation with dry air. Analgesic effects of acetaminophen and acetaminophen plus caffeine but not caffeine alone caused a significant reduction of pain‐related cortical potentials beginning 30 minutes after medication. The combination demonstrated an enhanced effect throughout the observation time up to 3 hours. Caffeine accelerated acetaminophen absorption, indicated by enhanced early AUCs. Significant analgesic effects of the combination on tonic pain ratings were found throughout the observation time as compared to acetaminophen and placebo. In this study, caffeine enhanced and prolonged the analgesic activity of acetaminophen.

Aceclofenac spares cyclooxygenase 1 as a result of limited but sustained biotransformation to diclofenac

The mechanism of action of aceclofenac is currently unclear. This study investigated whether biotransformation to metabolites (4′‐hydroxy‐aceclofenac, diclofenac, 4′‐hydroxy‐diclofenac) contributes to inhibitory effects on the cyclooxygenase (COX) isozymes in vitro and ex vivo.

Determinants of Steady-State Torasemide Pharmacokinetics Impact of Pharmacogenetic Factors, Gender and Angiotensin II Receptor Blockers

AbstractBackground: Torasemide is frequently used for the treatment of hypertension and heart failure. However, the determinants of torasemide pharmacokinetics in patients during steady-state conditions are largely unknown. We therefore explored the impact of genetic polymorphisms of cytochrome P450 (CYP) 2C9 (CYP2C9) and organic anion transporting polypeptide (OATP) 1B1 (SLCO1B1), gender, and the effects of losartan and irbesartan comedication on the interindividual variability of steady-state pharmacokinetics of torasemide. Patients and methods: Twenty-four patients receiving stable medication with torasemide 10 mg once daily and with an indication for additional angiotensin II receptor blocker (ARB) treatment to control hypertension or to treat heart failure were selected. Blood samples were taken before torasemide administration and 0.5, 1, 2, 4, 8, 12 and 24 hours after administration. After this first study period, patients received either irbesartan 150 mg (five female and seven male patients aged 69 ± 8 years) or losartan 100 mg (two female and ten male patients aged 61 ± 8 years) once daily. After 3 days of ARB medication, eight blood samples were again collected at the timepoints indicated above. The patients’ long-term medications, which did not include known CYP2C9 inhibitors, were maintained at a constant dose during the study. All patients were genotyped for CYP2C9 (*1/*1 [n = 15]; *1/*2 [n = 4]; *1/*3 [n = 5]) as well as for SLCO1B1 (c.521TT [n = 13]; c.521TC [n = 11]). Results: Factorial ANOVA revealed an independent impact of the CYP2C9 genotype (dose-normalized area under the plasma concentration-time curve during the 24-hour dosing interval at steady state [AUC24,ss/D]: *1/*1 375.5 ± 151.4 μg · h/L/mg vs *1/*3 548.5 ± 271.6 μg · h/L/mg, p = 0.001), the SLCO1B1 genotype (AUC24,ss/D: TT 352.3 ± 114 μg · h/L/mg vs TC 487.6 ± 218.4 μg · h/L/mg, p < 0.05) and gender (AUC24,ss/D: males 359.5 ± 72.2 μg · h/L/mg vs females 547.3 ± 284 μg · h/L/mg, p < 0.01) on disposition of torasemide. Coadministration of irbesartan caused a 13% increase in the AUC24,ss/D of torasemide (p = 0.002), whereas losartan had no effect. Conclusion: This study shows that the CYP2C9*3 and SLCO1B1 c.521TC genotype and female gender are significant and independent predictors of the pharmacokinetics of torasemide. Coadministration of irbesartan yields moderate but significant increases in the torasemide plasma concentration and elimination half-life.

Single-dose nimodipine normalizes impaired retinal circulation in normal tension glaucoma.

Purpose:Several studies indicate that calcium channel blockers improve the clinical course of normal tension glaucoma (NTG), whereas the underlying mechanism is not fully investigated. Hemodynamic improvement and neuroprotective effects are discussed. In this study, we measured the hemodynamic effects of nimodipine on retinal circulation. Patients and Methods:Sixteen patients with NTG and clinical signs of vasospastic hyperreactivity, such as suffering from extremely cold hands and feet, were consecutively selected out of the local glaucoma registry. Ten healthy age-matched volunteers were included as controls. Retinal capillary blood flow was measured by Scanning Laser Doppler Flowmetry in both eyes before and 90 ± 10 minutes after a single oral dose of 30 mg nimodipine. Results:Before administration of nimodipine, retinal capillary blood flow was significantly reduced in NTG patients compared with controls (262 ± 80 vs. 487 ± 164 AU, P < 0.001). Nimodipine increased retinal capillary blood flow in NTG patients by 91 ± 73% (P < 0.001) to values of healthy controls (440 ± 113 vs. 439 ± 123 AU, P = 0.635). In controls, nimodipine did not show significant effects. Conclusions:In NTG patients with additional vasospastic symptoms, retinal capillary blood is significantly reduced in comparison with healthy controls. Single-dose nimodipine yields to a normalization of retinal circulation in NTG patients up to values of healthy controls 90 minutes after drug administration.

Selective and rapid liquid chromatography-mass spectrometry method for the quantification of rofecoxib in pharmacokinetic studies with humans.

An easy, rapid and selective method for the determination of rofecoxib in human plasma is presented. The analytical technique is based on reversed-phase high-performance liquid chromatography coupled to atmospheric pressure chemical ionisation mass spectrometry (Finnigan Mat LCQ ion trap). The retention time of rofecoxib was 1.2 min. The method has been validated over a linear range from 1 to 500 microg/l using celecoxib as internal standard. After validation, the method was used to study the pharmacokinetic profile of rofecoxib in 12 healthy volunteers after administration of a single oral dose (12.5 mg). The presented method was sufficient to cover more than 95% of the area under the curve. The pharmacokinetic characteristics (mean+/-SD) were tmax: 2.4+/-1.0 h, Cmax: 147+/-34 microg/l, AUCinfinity: 2038+/-581 microg h/l and t 1/2: 11.3+/-2.1 h.

Tolerability of β‐blockers metabolized via cytochrome P450 2D6 is sex‐dependent

möller J. Enantiospecific effects of cytochrome P450 2C9 amino acid variants on ibuprofen pharmacokinetics and on the inhibition of cyclooxygenases 1 and 2. Clin Pharmacol Ther 2002;72:62-75. 4. Martinez C, Blanco G, Ladero JM, Garcia-Martin E, Taxonera C, Gamito FG, et al. Genetic predisposition to acute gastrointestinal bleeding after NSAIDs use. Br J Pharmacol 2004;141:205-8. 5. Chan AT, Giovannucci EL, Meyerhardt JA, Schernhammer ES, Curhan GC, Fuchs CS. Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer. JAMA 2005;294:914-23. 6. Ulrich CM, Bigler J, Potter JD. Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nat Rev Cancer 2006;6:130-40.