QT time prolongation
Adverse drug events
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Explanations of the substances for patients
We have no additional warnings for the combination of methadone and loratadine. Please also consult the relevant specialist information.
|Methadone||1 [1,1.82] 1||1|
The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. We do not expect any change in exposure for methadone, when combined with loratadine (100%). The AUC is between 100% and 182% depending on the CYP2B6
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Methadone has a mean oral bioavailability [ F ] of 75%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather long at 35 hours and constant plasma levels [ Css ] are only reached after more than 140 hours. The protein binding [ Pb ] is moderately strong at 87.5% and the volume of distribution [ Vd ] is very large at 330 liters. Since the substance has a low hepatic extraction rate of 0.12, displacement from protein binding [Pb] in the context of an interaction can lead to increased exposure. About 37.5% of an administered dose is excreted unchanged via the kidneys and this proportion is seldom changed by interactions. The metabolism takes place via CYP1A2, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6 and CYP3A4, among others and the active transport takes place in particular via PGP.
Loratadine has a low oral bioavailability [ F ] of 10%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The protein binding [ Pb ] is 98% strong. The metabolism takes place via CYP2D6 and CYP3A4, among others and the active transport takes place in particular via PGP.
|Serotonergic Effects a||1||+||Ø|
Recommendation: As a precautionary measure, symptoms of serotonergic overstimulation should be taken into account, especially after increasing the dose and at doses in the upper therapeutic range.
Rating: Methadone has a mild effect on the serotonergic system. The risk of a serotonergic syndrome can be classified as low with this medication if the dosage is in the usual range. According to our knowledge, loratadine does not increase serotonergic activity.
|Kiesel & Durán b||2||+||+|
Recommendation: As a precaution, attention should be paid to anticholinergic symptoms, especially after increasing the dose and at doses in the upper therapeutic range.
Rating: Methadone and loratadine only have a mild effect on the anticholinergic system. The risk of anticholinergic syndrome with this medication is rather low if the dosage is in the usual range.
QT time prolongation
Rating: Methadone can potentially trigger torsades de pointes ventricular arrhythmias. We do not know of any QT-prolonging potential for loratadine.
General adverse effects
|Side effects||∑ frequency||met||lor|
|Urinary retention||10.0 %||10.0||n.a.|
Fatigue (3%): loratadine
Adrenal insufficiency: methadone
Hypersensitivity reaction: methadone
Respiratory arrest: methadone
Respiratory depression: methadone
Based on your answers and scientific information, we assess the individual risk of undesirable side effects. These recommendations are intended to advise professionals and are not a substitute for consultation with a doctor. In the restricted test version (alpha), the risk of all substances has not yet been conclusively assessed.
Abstract: This histological and immunohistochemical study of 6 food handlers affected by immediate contact dermatitis due to foods shows that apparently normal skin of patients with this condition presents several histological and immunohistochemical abnormalities. Skin biopsies of normal hand skin showed focal parakeratosis and moderately dense dermal infiltrates. Immunohistochemistry showed an increased number of Langerhans cells in the epidermis and in the superficial dermis and a mononuclear dermal infiltrate consisting of peripheral T lymphocytes with a CD4/CD8 ratio of 5-6/1. Biopsies of the immediate vesicular reactions induced by foods showed spongiotic vesicles within the epidermis and a moderate to dense mononuclear dermal perivascular infiltrate. The immunohistochemical features were similar to those described in apparently normal skin. The mechanism of this immediate vesicular reaction requires further research. The rapid appearance of the lesions (after 20-30 min) probably excludes an immunological cell-mediated pathogenesis. A non-immunological mechanism due to direct liberation of mediators by foods is more readily conceivable than an immediate immunological type of contact reaction.
Abstract: Concentrations of methadone in plasma, estimates of pain relief, and pupillary size were determined after a single intravenous dose (10 to 30 mg) of methadone hydrochloride to eight patients with chronic pain, five of whom had cancer. The pharmacokinetic parameter estimates reveal rapid and extensive distribution (Varea) and a slow apparent elimination half-life (t1/2) (mean Varea = 3.59 L/kg and harmonic mean t1/2 = 23 hours). The harmonic mean blood clearance is 106 ml/min, the harmonic mean renal clearance is 3.9 ml/min, the mean hepatic extraction ratio is 0.089, and plasma protein binding is 86% to 89%. These results suggest that only the free (unbound) fraction of methadone present in blood is extracted by the liver and that methadone can be classified as a low (hepatic)-extraction drug. The data were fit to a pharmacokinetic-pharmacodynamic model to obtain estimates of the steady-state plasma methadone concentration required to produce 50% of the maximum pain relief. This value varied from 0.04 to 1.13 micrograms/ml (mean = 0.29 micrograms/ml). These results indicate substantial interindividual variation in the relationship between changes in plasma methadone concentration and analgesia in patients with chronic pain receiving opioids. A pharmacokinetic-pharmacodynamic model may be useful for the individualization of analgesic dosage and therefore the optimization of pain management in patients with chronic pain.
Abstract: OBJECTIVE: To evaluate the effects of coadministration of loratadine and erythromycin on the pharmacokinetics and electrocardiographic repolarization (QTc) pharmacodynamics of loratadine and its metabolite descarboethoxyloratadine in healthy volunteers. METHODS: Twenty-four healthy volunteers were studied in a prospective, double-blind crossover design while confined in a Clinical Research Center. The primary pharmacodynamic end point of the study was the difference between baseline and day 10 mean QTc intervals obtained from surface electrocardiograms. Plasma concentrations of loratadine, descarboethoxyloratadine, and erythromycin were measured on treatment day 10 for pharmacokinetic analysis. Subjects received in random sequence the following three treatments for 10 consecutive days during three separate study periods: 10 mg loratadine every morning plus 500 mg erythromycin stearate every 8 hours, or 10 mg loratadine every morning plus placebo every 8 hours, or placebo every morning plus 500 mg erythromycin stearate. RESULTS: Concomitant administration of loratadine and erythromycin was associated with increased plasma concentrations of loratadine (40% increase in area under the plasma concentration-time curve [AUC]) and descarboethoxyloratadine (46% increase in AUC) compared with loratadine alone. Analysis of variance showed no difference between the treatment groups in effect on QTc intervals compared with baseline, and no significant change from baseline was observed. No clinically relevant changes in the safety profile of loratadine were observed, and there were no reports of sedation nor syncope. CONCLUSION: Although concomitant administration of loratadine and erythromycin was associated with increased plasma concentrations of loratadine and descarboethoxyloratadine, no clinically relevant changes in the safety profile of loratadine were observed. In this study, 10 mg loratadine administered orally for 10 consecutive days was well tolerated when coadministered with therapeutic doses of erythromycin stearate.
Abstract: AIMS: To evaluate whether ketoconazole or cimetidine alter the pharmacokinetics of loratadine, or its major metabolite, desloratadine (DCL), or alter the effects of loratadine or DCL on electrocardiographic repolarization in healthy adult volunteers. METHODS: Two randomized, evaluator-blind, multiple-dose, three-way crossover drug interaction studies were performed. In each study, subjects received three 10 day treatments in random sequence, separated by a 14 day washout period. The treatments were loratadine alone, cimetidine or ketoconazole alone, or loratadine plus cimetidine or ketoconazole. The primary study endpoint was the difference in mean QTc intervals from baseline to day 10. In addition, plasma concentrations of loratadine, DCL, and ketoconazole or cimetidine were obtained on day 10. RESULTS: Concomitant administration of loratadine and ketoconazole significantly increased the loratadine plasma concentrations (307%; 90% CI 205-428%) and DCL concentrations (73%; 62-85%) compared with administration of loratadine alone. Concomitant administration of loratadine and cimetidine significantly increased the loratadine plasma concentrations (103% increase; 70-142%) but not DCL concentrations (6% increase; 1-11%) compared with administration of loratadine alone. Cimetidine or ketoconazole plasma concentrations were unaffected by coadministration with loratadine. Despite increased concentrations of loratadine and DCL, there were no statistically significant differences for the primary electrocardiographic repolarization parameter (QTc) among any of the treatment groups. No other clinically relevant changes in the safety profile of loratadine were observed as assessed by electrocardiographic parameters (mean (90% CI) QTc changes: loratadine vs loratadine + ketoconazole = 3.6 ms (-2.2, 9.4); loratadine vs loratadine + cimetidine = 3.2 ms (-1.6, 7.9)), clinical laboratory tests, vital signs, and adverse events. CONCLUSIONS: Loratadine 10 mg daily was devoid of any effects on electrocardiographic parameters when coadministered for 10 days with therapeutic doses of ketoconazole or cimetidine in healthy volunteers. It is concluded that, although there was a significant pharmacokinetic drug interaction between ketoconazole or cimetidine and loratadine, this effect was not accompanied by a change in the QTc interval in healthy adult volunteers.
Abstract: STUDY OBJECTIVE: To investigate the relationship between the daily dose of the synthetic opioid methadone and the corrected QT (QTc) interval in a series of methadone-treated patients who developed torsade de pointes. DESIGN: Retrospective case series analysis. SETTING: Outpatient pain management center and methadone maintenance treatment programs. PATIENTS: Seventeen patients who developed torsade de pointes while receiving very high daily doses of methadone. MEASUREMENTS AND MAIN RESULTS: The QTc intervals were calculated for each patient. The relationship between daily methadone dose and QTc interval was assessed and adjusted for clinical characteristics that may have independently prolonged cardiac repolarization. The mean QTc interval was 615 +/- 77 msec. Multiple linear regression indicated that only the daily methadone dose was predictive of the QTc interval (r = +0.51, p = 0.03). All other variables examined, such as age, sex, presence of hypokalemia or structural heart disease, and presence of QT-prolonging drugs, were not predictive of the QTc interval (minimum p = 0.28). CONCLUSION: In this series, the daily methadone dose correlated positively with the QTc interval. This finding supports the possibility that methadone contributed to the development of arrhythmia.
Abstract: No Abstract available
Abstract: Understanding drug interactions between antiretrovirals and opiate therapies may decrease toxicities and enhance adherence, with improved HIV outcomes in injection drug users. We report results of a clinical pharmacology study designed to examine the interaction of the protease inhibitor, nelfinavir, with methadone and LAAM (N = 48). Nelfinavir decreased methadone exposure, but no withdrawal was observed over the five day study period. LAAM and dinorLAAM concentrations were decreased, while norLAAM concentrations were increased, with minimal overall change in LAAM/metabolite exposure. Methadone and LAAM did not affect nelfinavir concentrations, but methadone decreased M8 metabolite exposure. While no toxicities were observed, clinicians should be aware of the potential for drug interactions when patients require treatment with nelfinavir and these opiate medications.
Abstract: BACKGROUND: The disposition of the long-acting opioid methadone, used to prevent opiate withdrawal and treat short- and long-lasting pain, is highly variable. Methadone undergoes N -demethylation to the primary metabolite 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium (EDDP), catalyzed in vitro by intestinal, hepatic, and expressed cytochrome P450 (CYP) 3A4. However, the role of CYP3A4 in human methadone disposition in vivo is unclear. This investigation tested the hypothesis that CYP3A induction (or inhibition) would increase (or decrease) methadone metabolism and clearance in humans. METHODS: Healthy volunteers were studied in a randomized, balanced, 4-way crossover study. They received intravenous (IV) midazolam (to assess CYP3A4 activity) and then simultaneous oral deuterium-labeled and IV unlabeled methadone after pretreatment with rifampin (INN, rifampicin) (hepatic/intestinal CYP3A induction), troleandomycin (hepatic/intestinal CYP3A inhibition), grapefruit juice (selective intestinal CYP3A inhibition), or nothing. Methadone effects were measured by dark-adapted pupil diameter. CYP isoforms catalyzing methadone metabolism by human liver microsomes and expressed CYPs in vitro were also evaluated. RESULTS: Methadone had high oral bioavailability (70%) and low intestinal (22%) and hepatic (9%) extraction, and there was a significant correlation ( r = 0.94, P <.001) between oral bioavailability and intestinal (but not hepatic) availability. Rifampin decreased bioavailability and oral and IV methadone plasma concentrations and increased IV clearance (4.42 +/- 1.00 mL. kg -1. min -1 versus 1.61 +/- 0.67 mL. kg -1. min -1, P <.05) and oral clearance (8.50 +/- 3.68 mL. kg -1. min -1 versus 2.05 +/- 0.92 mL. kg -1. min -1, P <.05), EDDP/methadone area under the curve (AUC) ratios, EDDP formation clearances, and hepatic extraction (0.27 +/- 0.06 versus 0.09 +/- 0.04, P <.05). Troleandomycin and grapefruit juice decreased the EDDP/methadone AUC ratio after oral methadone (0.17 +/- 0.10 and 0.14 +/- 0.06 versus 0.27 +/- 0.20, P <.05) but not IV methadone and had no effect on methadone plasma concentrations, IV clearance (1.29 +/- 0.41 mL. kg -1. min -1 and 1.48 +/- 0.55 mL. kg -1. min -1 ) or oral clearance (2.05 +/- 1.52 mL. kg -1. min -1 and 1.89 +/- 1.07 mL. kg -1. min -1 ), or other kinetic parameters. There was no correlation between methadone clearance and hepatic CYP3A4 activity. Pupil diameter changes reflected plasma methadone concentrations. In vitro experiments showed a predominant role for both CYP3A4 and CYP2B6 in liver microsomal methadone N -demethylation. CONCLUSION: First-pass intestinal metabolism is a determinant of methadone bioavailability. Intestinal and hepatic CYP3A activity only slightly affects human methadone N -demethylation but has no significant effect on methadone concentrations, clearance, or clinical effects. Greater rifampin effects, compared with troleandomycin and grapefruit juice, on methadone disposition suggest a major role for intestinal transporters and for other CYPs, such as CYP2B6. Interindividual variability and drug interactions affecting intestinal transporter and hepatic CYP3A and CYP2B6 activity may alter methadone disposition.
Abstract: This article reviews the unique pharmacological properties of methadone and outlines its appropriate clinical application, with focus upon its use in the treatment of chronic pain. Although methadone is most widely known for its use in the treatment of opioid dependence, methadone also provides effective analgesia. Patients who experience inadequate pain relief or intolerable side effects with other opioids or who suffer from neuropathic pain may benefit from a transition to methadone as their analgesic agent. Adverse effects, particularly respiratory depression and death, make a fundamental knowledge of methadone's pharmacological properties essential to the provider considering methadone as analgesic therapy for a patient with chronic pain.
Abstract: Methadone is a synthetic opioid with potent analgesic effects. Although it is associated commonly with the treatment of opioid addiction, it may be prescribed by licensed family physicians for analgesia. Methadone's unique pharmacokinetics and pharmacodynamics make it a valuable option in the management of cancer pain and other chronic pain, including neuropathic pain states. It may be an appropriate replacement for opioids when side effects have limited further dosage escalation. Metabolism of and response to methadone varies with each patient. Transition to methadone and dosage titration should be completed slowly and with frequent monitoring. Conversion should be based on the current daily oral morphine equivalent dosage. After starting methadone therapy or increasing the dosage, systemic toxicity may not become apparent for several days. Some medications alter the absorption or metabolism of methadone, and their concurrent use may require dosing adjustments. Methadone is less expensive than other sustained-release opioid formulations.
Abstract: Loratadine is known to be a substrate for both CYP3A4 and CYP2D6 based on a previous in vitro study. In view of the large interindividual variability in loratadine pharmacokinetics and the greater genetically determined variability of CYP2D6 activity than of CYP3A4 in vivo, we hypothesized that CYP2D6 polymorphisms may contribute to the pharmacokinetic variability of loratadine. The purpose of this study was to evaluate the effect of CYP2D6 genotype (specifically the CYP2D6*10 allele) on the pharmacokinetics of loratadine in Chinese subjects. Three groups of healthy male Chinese subjects were enrolled: group I, homozygous CYP2D6*1 (*1/*1, n=4); group II, heterozygous CYP2D6*10 (*1/*10 or *2/*10, n=6); and group III, homozygous CYP2D6*10 (*10/*10, n=7) carriers. Each subject received a single oral dose of 20 mg of loratadine under fasting conditions. Multiple blood samples were collected over 48 h, and the plasma concentrations of loratadine and its metabolite desloratadine were determined by high-performance liquid chromatography. In comparing homozygous CYP2D6*10 (group III) to heterozygous CYP2D6*10 (group II) to homozygous CYP2D6*1 (group I) subjects, loratadine oral clearance values were 7.17+/- 2.54 versus 11.06+/-1.70 versus 14.59+/-2.43 l/h/kg, respectively [one-way analysis of variance (ANOVA), p<0.01], and the corresponding metabolic ratios [area under the plasma concentration-time curve (AUC)(desloratadine)/AUC(loratadine)] were 1.55+/-0.73 versus 2.47+/- 0.46 versus 3.32+/- 0.49, respectively (one-way ANOVA, p<0.05), indicating a gene-dose effect. The results demonstrated that CYP2D6 polymorphism prevalent in the Chinese population significantly affected loratadine pharmacokinetics.
Abstract: No Abstract available
Abstract: BACKGROUND: Metabolism and clearance of racemic methadone are stereoselective and highly variable, yet the mechanism remains largely unknown. Initial in vitro studies attributed methadone metabolism to cytochrome P4503A4 (CYP3A4). CYP3A4 was also assumed responsible for methadone clearance in vivo. Nevertheless, recent clinical data do not support a primary role for CYP3A4 and suggest that CYP2B6 may mediate methadone clearance. Expressed CYP2B6 and also CYP2C19 N-demethylate methadone in vitro. This investigation tested the hypothesis that CYPs 2B6, 3A4, and/or 2C19 are responsible for stereoselective methadone metabolism in human liver microsomes and in vivo. METHODS: N-demethylation of racemic methadone and individual enantiomers by expressed CYPs 2B6, 2C19, and 3A4 was evaluated. Stereoselective microsomal methadone metabolism was quantified, compared with CYP 2B6 and 3A4 content, and probed using CYP isoform-selective inhibitors. A crossover clinical investigation (control, CYP2B6 and CYP3A4 induction by rifampin, CYP3A inhibition by troleandomycin and grapefruit juice) evaluated stereoselective methadone disposition. RESULTS: At clinical concentrations, methadone enantiomer N-demethylation by recombinant CYPs 2B6, 3A4, and 2C19 was S > R, S = R, and S << R. Greater stereoselective metabolism (S > R) occurred in livers expressing high levels of CYP2B6 compared with CYP3A4. Clopidogrel, troleandomycin, and (+)-N-3-benzyl-nirvanol, selective inhibitors of CYPs 2B6, 3A4, and 2C19, respectively, inhibited microsomal methadone metabolism by 50-60%, 20-30%, and less than 10%. Only inhibition by clopidogrel was stereoselective. Clinically, rifampin diminished both R- and S-methadone plasma concentrations, but troleandomycin and grapefruit juice altered neither R- nor S-methadone concentrations. Plasma R/S-methadone ratios were increased by rifampin but unchanged by CYP3A inhibition. CONCLUSIONS: These results suggest a significant role for CYP2B6, but not CYP3A, in stereoselective human methadone metabolism and disposition.
Abstract: BACKGROUND: This topical review addresses methadone's pharmacology, its application in malignant and non-malignant pain conditions, practical issues related to methadone for the treatment of pain and its influence on QTc time. METHODS: Relevant papers were identified in PubMed and EMBASE. RESULTS: Methadone is advocated by experts as a second line opioid when first line opioids fail to provide a satisfactory balance between pain control and side effects (opioid switching). Although randomized-controlled studies are lacking, current evidence suggests that switching to methadone in this situation reduces pain intensity. However, interindividual variability in its pharmacokinetics make its application challenging and metabolism by CYP 3A4 and 2B6 implies a substantial risk of drug-drug interactions. Several ways of switching to methadone have been presented, with a gradual switch during 3 days or 'stop and go' as the dominating strategies. Episodes of torsade de pointes arrhythmia during methadone treatment have been reported in patients with other risk factors for arrhythmia, while small prospective studies have reported a small, lasting and stable increase in QTc time. The extensive use of methadone for opioid replacement in addicts has added additional patient barriers to its use for pain control. CONCLUSION: In spite of challenges related to the variable pharmacokinetics and concerns regarding increase in QTc time, current evidence indicates that opioid switching to methadone improves pain control in a substantial proportion of patients who are candidates for opioid switching. Measures must be instituted to secure that patients receiving methadone for pain are not considered opioid addicts.
Abstract: BACKGROUND: Adverse effects of anticholinergic medications may contribute to events such as falls, delirium, and cognitive impairment in older patients. To further assess this risk, we developed the Anticholinergic Risk Scale (ARS), a ranked categorical list of commonly prescribed medications with anticholinergic potential. The objective of this study was to determine if the ARS score could be used to predict the risk of anticholinergic adverse effects in a geriatric evaluation and management (GEM) cohort and in a primary care cohort. METHODS: Medical records of 132 GEM patients were reviewed retrospectively for medications included on the ARS and their resultant possible anticholinergic adverse effects. Prospectively, we enrolled 117 patients, 65 years or older, in primary care clinics; performed medication reconciliation; and asked about anticholinergic adverse effects. The relationship between the ARS score and the risk of anticholinergic adverse effects was assessed using Poisson regression analysis. RESULTS: Higher ARS scores were associated with increased risk of anticholinergic adverse effects in the GEM cohort (crude relative risk [RR], 1.5; 95% confidence interval [CI], 1.3-1.8) and in the primary care cohort (crude RR, 1.9; 95% CI, 1.5-2.4). After adjustment for age and the number of medications, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM cohort (adjusted RR, 1.3; 95% CI, 1.1-1.6; c statistic, 0.74) and in the primary care cohort (adjusted RR, 1.9; 95% CI, 1.5-2.5; c statistic, 0.77). CONCLUSION: Higher ARS scores are associated with statistically significantly increased risk of anticholinergic adverse effects in older patients.
Abstract: OBJECTIVES: To examine the longitudinal relationship between cumulative exposure to anticholinergic medications and memory and executive function in older men. DESIGN: Prospective cohort study. SETTING: A Department of Veterans Affairs primary care clinic. PARTICIPANTS: Five hundred forty-four community-dwelling men aged 65 and older with diagnosed hypertension. MEASUREMENTS: The outcomes were measured using the Hopkins Verbal Recall Test (HVRT) for short-term memory and the instrumental activity of daily living (IADL) scale for executive function at baseline and during follow-up. Anticholinergic medication use was ascertained using participants' primary care visit records and quantified as total anticholinergic burden using a clinician-rated anticholinergic score. RESULTS: Cumulative exposure to anticholinergic medications over the preceding 12 months was associated with poorer performance on the HVRT and IADLs. On average, a 1-unit increase in the total anticholinergic burden per 3 months was associated with a 0.32-point (95% confidence interval (CI)= 0.05-0.58) and 0.10-point (95% CI=0.04-0.17) decrease in the HVRT and IADLs, respectively, independent of other potential risk factors for cognitive impairment, including age, education, cognitive and physical function, comorbidities, and severity of hypertension. The association was attenuated but remained statistically significant with memory (0.29, 95% CI=0.01-0.56) and executive function (0.08, 95% CI=0.02-0.15) after further adjustment for concomitant non-anticholinergic medications. CONCLUSION: Cumulative anticholinergic exposure across multiple medications over 1 year may negatively affect verbal memory and executive function in older men. Prescription of drugs with anticholinergic effects in older persons deserves continued attention to avoid deleterious adverse effects.
Abstract: BACKGROUND: Methadone clearance is highly variable, and drug interactions are problematic. Both have been attributed to CYP3A, but actual mechanisms are unknown. Drug interactions can provide such mechanistic information. Ritonavir/indinavir, one of the earliest protease inhibitor combinations, may inhibit CYP3A. We assessed ritonavir/indinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A activity, and intestinal transporters (P-glycoprotein) activity. CYP3A and transporters were assessed with alfentanil and fexofenadine, respectively. METHODS: Twelve healthy human immunodeficiency virus-negative volunteers underwent a sequential three-part crossover. On three consecutive days, they received oral alfentanil/fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone, repeated after acute (3 days) and steady-state (2 weeks) ritonavir/indinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were assessed by miosis. RESULTS: Alfentanil apparent oral clearance was inhibited more than 97% by both acute and steady-state ritonavir/indinavir, and systemic clearance was inhibited more than 90% due to diminished hepatic and intestinal extraction. Ritonavir/indinavir increased fexofenadine area under the plasma concentration-time curve four- to five-fold, suggesting significant inhibition of gastrointestinal P-glycoprotein. Ritonavir/indinavir slightly increased methadone N-demethylation, but it had no significant effects on methadone plasma concentrations or on systemic or apparent oral clearance, renal clearance, hepatic extraction or clearance, or bioavailability. Ritonavir/indinavir had no significant effects on methadone plasma concentration-effect relationships. CONCLUSIONS: Inhibition of both hepatic and intestinal CYP3A activity is responsible for ritonavir/indinavir drug interactions. Methadone disposition was unchanged, despite profound inhibition of CYP3A activity, suggesting little or no role for CYP3A in clinical methadone metabolism and clearance. Methadone bioavailability was unchanged, despite inhibition of gastrointestinal P-glycoprotein activity, suggesting that this transporter does not limit methadone intestinal absorption.
Abstract: BACKGROUND: Methadone plasma concentrations are decreased by nelfinavir. Methadone clearance and the drug interactions have been attributed to CYP3A4, but actual mechanisms of methadone clearance and the nelfinavir interaction are unknown. We assessed nelfinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A4/5 activity, and intestinal P-glycoprotein transport activity. CYP3A4/5 and transporters were assessed using alfentanil and fexofenadine, respectively. METHODS: Twelve healthy HIV-negative volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral methadone. This was repeated after nelfinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by pupil diameter change (miosis). RESULTS: Nelfinavir decreased intravenous and oral methadone plasma concentrations 40-50%. Systemic clearance, hepatic clearance, and hepatic extraction all increased 1.6- and 2-fold, respectively, for R- and S-methadone; apparent oral clearance increased 1.7- and 1.9-fold. Nelfinavir stereoselectively increased (S>R) methadone metabolism and metabolite formation clearance, and methadone renal clearance. Methadone bioavailability and P-glycoprotein activity were minimally affected. Nelfinavir decreased alfentanil systemic and apparent oral clearances 50 and 76%, respectively. Nelfinavir appeared to shift the methadone plasma concentration-effect (miosis) curve leftward and upward. CONCLUSIONS: Nelfinavir induced methadone clearance by increasing renal clearance, and more so by stereoselectively increasing hepatic metabolism, extraction and clearance. Induction occurred despite 50% inhibition of hepatic CYP3A4/5 activity and more than 75% inhibition of first-pass CYP3A4/5 activity, suggesting little or no role for CYP3A in clinical methadone disposition. Nelfinavir may alter methadone pharmacodynamics, increasing clinical effects.
Abstract: The present study demonstrated that in addition to CYP3A4 and CYP2D6, the metabolism of loratadine is also catalyzed by CYP1A1, CYP2C19, and to a lesser extent by CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP3A5. The biotransformation of loratadine was associated with the formation of desloratadine (DL) and further hydroxylation of both DL and the parent drug (loratadine). Based on the inhibition and correlation studies contribution of CYP2C19 in the formation of the major circulating metabolite DL seems to be minor. Reported clinical results suggest that the steady state mean (%CV) plasma Cmax and AUC(24hr) of loratadine were 4.73 ng/ml (119%) and 24.1 ng.hr/ml (157%), respectively, after dosing with 10 mg loratadine tablets for 10 days. High inter-subject variability in loratadine steady-state data is probably due to the phenotypical characteristics of CYP2D6, CYP2C19, and CYP3A4. The relative abundance of CYP3A4 in the human liver exceeds that of CYP2C19 and CYP2D6 and therefore the contribution of CYP3A4 in the metabolism of loratadine should be major (approximately 70%).
Abstract: Numerous established and potential drug interactions with methadone are clinically important in people treated with methadone either for addiction or for chronic pain. Methadone users often have comorbidities and are prescribed drugs that may interact with methadone. Methadone is extensively metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP 1A2, 2D6, 2D8, 2C9/2C8, 2C19, and 2B6. Eighty-six percent of methadone is protein bound, predominately to α1-acid glycoprotein (AGP). Polymorphisms in or interactions with CYPs that metabolize methadone, changes in protein binding, and other pathophysiological conditions affect the pharmacokinetic properties of methadone. It is critical for health care providers who treat patients on methadone to have adequate information on the interactions of methadone with other drugs of abuse and other medications. We set out to describe drug-drug interactions as well as physiological and pathophysiological factors that may impact the pharmacokinetics of methadone. Using MEDLINE, we conducted a systematic search for papers and related abstracts published between 1966 and June 2010. Keywords that included methadone, drug-drug interactions, CYP P450 and AGP identified a total of 7709 papers. Other databases, including the Cochrane Database of Systematic Reviews and Scopus, were also searched; an additional 929 papers were found. Final selection of 286 publications was based on the relevance of each paper to the topic. Over 50 such interactions were found. Interactions of methadone with other drugs can lead to increased or decreased methadone drug levels in patients and result in potential overdose or withdrawal, respectively. The former can contribute to methadone's fatality. Prescribers of methadone and pharmacists should enquire about any new medications (including natural products and over-the-counter medications) periodically, and especially when an otherwise stable patient suddenly experiences drug craving, withdrawal or intoxication.
Abstract: BACKGROUND: Anticholinergic drugs put elderly patients at a higher risk for falls, cognitive decline, and delirium as well as peripheral adverse reactions like dry mouth or constipation. Prescribers are often unaware of the drug-based anticholinergic burden (ACB) of their patients. This study aimed to develop an anticholinergic burden score for drugs licensed in Germany to be used by clinicians at prescribing level. METHODS: A systematic literature search in pubmed assessed previously published ACB tools. Quantitative grading scores were extracted, reduced to drugs available in Germany, and reevaluated by expert discussion. Drugs were scored as having no, weak, moderate, or strong anticholinergic effects. Further drugs were identified in clinical routine and included as well. RESULTS: The literature search identified 692 different drugs, with 548 drugs available in Germany. After exclusion of drugs due to no systemic effect or scoring of drug combinations (n = 67) and evaluation of 26 additional identified drugs in clinical routine, 504 drugs were scored. Of those, 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects. CONCLUSIONS: The newly created ACB score for drugs authorized in Germany can be used in daily clinical practice to reduce potentially inappropriate medications for elderly patients. Further clinical studies investigating its effect on reducing anticholinergic side effects are necessary for validation.