Objective The aim was to develop a drug-drug interaction database (SFINX) to be integrated into decision support systems or to be used in website solutions for clinical evaluation of interactions. Methods Key elements such as substance properties and names, drug formulations, text structures and references were defined before development of the database. Standard operating procedures for literature searches, text writing rules and a classification system for clinical relevance and documentation level were determined. ATC codes, CAS numbers and country-specific codes for substances were identified and quality assured to ensure safe integration of SFINX into other data systems. Much effort was put into giving short and practical advice regarding clinically relevant drug-drug interactions.Results SFINX includes over 8,000 interaction pairs and is integrated into Swedish and Finnish computerised decision support systems. Over 31,000 physicians and pharmacists are receiving interaction alerts through SFINX. User feedback is collected for continuous improvement of the content. Conclusion SFINX is a potentially valuable tool delivering instant information on drug interactions during prescribing and dispensing.
The effect of oral contraceptives (OCs) on melatonin metabolism was studied in 29 subjects genotyped for CYP1A2 SNP g.-163C>A polymorphism. Plasma melatonin and 6-OH-melatonin concentrations were measured after a 6-mg dose of melatonin using a validated liquid chromatography/mass spectrometry method. The mean melatonin AUC and C(max) values were 4- to 5-fold higher in OC users than in non-OC users (P < .0001), whereas the weight-adjusted clearance was significantly lower in OC users (P < .0001). No significant difference in melatonin pharmacokinetics between the genotypes and no additional effect by the genotype on the OC-induced increase in melatonin exposure were evident. Melatonin exposure had no significant effect on the subjects' state of alertness. In conclusion, a significant inhibitory effect of OCs on the CYP1A2-catalyzed melatonin metabolism was seen; thereby, OC use can alter CYP1A2-phenotyping results.
PurposeThe aims of this study are to describe the development of PHARAO (Pharmacological Risk Assessment Online), a decision support system providing a risk profile for adverse events, associated with combined effects of multiple medicines, and to present data from a pilot study, testing the use, functionality, and acceptance of the PHARAO system in a clinical setting.MethodsAbout 1400 substances were scored in relation to their risk to cause any of nine common and/or serious adverse effects. Algorithms for each adverse effect score were developed to create individual risk profiles from the patient’s list of medication. The system was tested and integrated to the electronic medical record, during a 4-month period in two geriatric wards and three primary healthcare centers, and a questionnaire was answered by the users before and after the test period.ResultsA total of 732 substances were tagged with one or more of the nine risks, most commonly with the risk of sedation or seizures. During the pilot, the system was used 933 times in 871 patients. The most common signals generated by PHARAO in these patients were related to the risks of constipation, sedation, and bleeding. A majority of responders considered PHARAO easy to use and that it gives useful support in performing medication reviews.ConclusionsThe PHARAO decision support system, designed as a complement to a database on drug-drug interactions used nationally, worked as intended and was appreciated by the users during a 4-month test period. Integration aspects need to be improved to minimize unnecessary signaling.
Earlier evidence suggests that melatonin is almost exclusively metabolised by CYP1A2 and could serve as a probe drug for CYP1A2 phenotyping. However, caffeine inhibits the metabolism of melatonin by CYP1A2 and dietary caffeine could be a potential confounder for the measurement of CYP1A2 activity with melatonin. We undertook a 3-phase cross-over study in 12 healthy volunteers to examine whether caffeine (200 mg single dose), taken 12 hr or 24 hr prior to melatonin intake, would affect the results of CYP1A2 phenotyping results as assessed by a spot sample melatonin concentration 1.5 hr after intake of 6 mg of melatonin orally. In addition we examined the influence of the CYP1A2*1F polymorphism on the phenotyping results by combining the present material with another 12 persons from a previous study. Caffeine, co-administered 12 or 24 hr prior to melatonin intake, did not have any significant effect on the 1.5 hr melatonin concentration (PΩ0.086 for ANOVA), but in two volunteers about 4 times increase in melatonin concentration was observed after caffeine intake 12 hr (but not 24 hr) before phenotyping with melatonin. Also, individuals homozygous for the CYP1A2*1A allele had clearly higher 1.5 hr melatonin concentration compared with the *1F/*1F or the *1F/*1A genotypes. Abstinence from caffeine for 24 hr prior to melatonin intake should be enough to overcome the possible confounding effect of caffeine on the CYP1A2 phenotyping with melatonin. Also, melatonin may be a sensitive probe to detect phenotypic differences with regard to CYP1A2*1F polymorphism. Melatonin might be, thus, advantageous for CYP1A2 phenotyping compared to the standard probe caffeine.
This study investigated the effect of voriconazole, an inhibitor of cytochrome P450 2C9 (CYP2C9) and CYP3A4, and itraconazole, an inhibitor of CYP3A4, on the pharmacokinetics and pharmacodynamics of meloxicam. Twelve healthy volunteers in a crossover study ingested 15 mg of meloxicam without pretreatment (control), after voriconazole pretreatment, and after itraconazole pretreatment. The plasma concentrations of meloxicam, voriconazole, itraconazole, and thromboxane B 2 (TxB 2 ) generation were monitored. Compared to the control phase, voriconazole increased the mean area under the plasma concentration-time curve from 0 to 72 h (AUC 0-72 ) of meloxicam by 47% (P < 0.001) and prolonged its mean half-life (t 1/2 ) by 51% (P < 0.01), without affecting its mean peak concentration (C max ). In contrast, itraconazole decreased the mean AUC 0-72 and C max of meloxicam by 37% (P < 0.001) and by 64% (P < 0.001), respectively, and prolonged its t 1/2 and time to C max . The plasma protein unbound fraction of meloxicam was unchanged by voriconazole and itraconazole. Lowered plasma meloxicam concentrations during the itraconazole phase were associated with decreased pharmacodymic effects of meloxicam, as observed by weaker inhibition of TxB 2 synthesis compared to the control and voriconazole phases. Voriconazole increases plasma concentrations of meloxicam, whereas itraconazole, unexpectedly, decreases plasma meloxicam concentrations, possibly by impairing its absorption.Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) of the oxicam class with selectivity toward cyclo-oxygenase 2 (COX-2) compared to 19). It is widely used in the treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and other rheumatological conditions. Meloxicam has an oral bioavailability of 89%, and its maximum plasma concentrations (C max ) are achieved within 4 to 11 h (10, 26). It is extensively bound to plasma proteins (Ͼ99%), mainly to albumin (24). The elimination half-life (t 1/2 ) of meloxicam ranges from 13 to 20 h, and it is suitable for once-daily dosing (24,26). Meloxicam is extensively metabolized in the liver, primarily by polymorphic cytochrome P450 2C9 (CYP2C9) enzyme, and to a minor extent by CYP3A4 enzyme, to four pharmacologically inactive metabolites (6, 24). Only negligible amounts of the parent drug are found in urine and in feces (24). The effect of different genotypes on the pharmacokinetics of meloxicam is not known.Voriconazole is a triazole antifungal agent used both intravenously and orally to treat invasive fungal infections. Voriconazole undergoes extensive oxidative metabolism involving CYP enzymes CYP2C19, CYP2C9, and CYP3A4 (13). Voriconazole is also an inhibitor of CYP2C9, CYP3A4, and CYP2C19 catalyzed reactions both in vitro and in vivo (17,21,23,25). Another triazole antifungal, itraconazole, is a potent inhibitor of CYP3A4 (18, 28), but it is without effect on CYP2C9 in humans (15,27).Because both voriconazole and itraconazole inhibit CYP enzymes involved in the metabolism of meloxicam, ...
AimsOur objective was to study in vivo the role of CYP2C and CYP3A4 in the disposition of 3-keto-desogestrel after administration of desogestrel, by using the selective inhibitors fluconazole (CYP2C) and itraconazole (CYP3A4). MethodsThis study had a three-way crossover design and included 12 healthy females, the data from 11 of whom were analyzed. In the first (control) phase all subjects received a single 150 m g oral dose of desogestrel alone. In the second and third phases subjects received a 4 day pretreatment with either 200 mg fluconazole or 200 mg itraconazole once daily in a randomized balanced order. Desogestrel was given 1 h after the last dose of the CYP inhibitor. Plasma 3-keto-desogestrel concentrations were determined for up to 72 h post dose. ResultsPretreatment with itraconazole for 4 days significantly increased the area under the plasma concentration-time curve (AUC) of 3-keto-desogestrel by 72.4% (95% confidence interval on the difference 12%, 133%; P = 0.024) compared with the control phase, whereas fluconazole pretreatment had no significant effect (95% CI on the difference -42%, 34%). Neither enzyme inhibitor affected significantly the maximum concentration (95% CI on the difference 14%, 124% for itraconazole and -23%, 40% for fluconazole) or elimination half-life (95% CI on the difference -42%, 120% for itraconazole and -24%, 61% for fluconazole) of 3-keto-desogestrel. ConclusionsAccording to the present study, the biotransformation of desogestrel to 3-ketodesogestrel did not appear to be mediated by CYP2C9 and CYP2C19 as suggested earlier. However, the further metabolism of 3-keto-desogestrel seems to be catalyzed by CYP3A4.
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