Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Jul 2011
Genetically polymorphic OCT1: another piece in the puzzle of the variable pharmacokinetics and pharmacodynamics of the opioidergic drug tramadol.
We investigated whether tramadol or its active metabolite, O-desmethyltramadol, are substrates of the organic cation transporter OCT1 and whether polymorphisms in OCT1 affect tramadol and O-desmethyltramadol pharmacokinetics. Tramadol showed high permeability through parallel artificial membrane permeability assays (PAMPAs). Tramadol uptake in HEK293 cells did not change after OCT1 overexpression, and the concentrations of tramadol in the plasma of healthy volunteers were independent of their OCT1 genotypes. ⋯ This increase in uptake was reversed by OCT1 inhibitors and absent when loss-of-function OCT1 variants were overexpressed. Volunteers carrying loss-of-function OCT1 polymorphisms had significantly higher plasma concentrations of O-desmethyltramadol (P = 0.002, n = 41) and significantly prolonged miosis, a surrogate marker of opioidergic effects (P = 0.005, n = 24). In conclusion, polymorphisms in OCT1 influence the pharmacokinetics of O-desmethyltramadol, presumably by affecting its uptake into liver cells, and thus may modulate the efficacy of tramadol treatment.
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Clin. Pharmacol. Ther. · Jul 2011
Alendronate adherence and its impact on hip-fracture risk in patients with established osteoporosis in Taiwan.
A pharmacoepidemiology study was conducted using the health insurance database in Taiwan to assess compliance with osteoporosis drug regimens and the impact of compliance on the risk for secondary fractures. Patients >50 years of age with vertebral/hip fracture who had been started on alendronate therapy for the first time only after the fracture were included. Compliance was measured using the medication possession ratio (MPR) and was included as a time-dependent covariate in the Cox model to compare the difference between compliant (MPR ≥ 80%) and noncompliant patients (MPR <80%) with respect to risk for subsequent hip fractures. ⋯ Over the 4-year follow-up period, the risk of hip fracture among the compliant patients was 70% lower than that among the noncompliant ones (adjusted hazard ratio (HR) 0.30). Among patients with osteoporosis in Taiwan who had experienced a fracture and had started alendronate therapy, compliance with the dosage regimen was suboptimal. It was also found that compliance significantly reduced the risk of secondary hip fracture up to 4 years.
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Clin. Pharmacol. Ther. · Mar 2011
Randomized Controlled Trial Comparative StudySubjective and physiological effects after controlled Sativex and oral THC administration.
Sativex is a cannabis-plant extract delivering nearly 1:1 Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) by oromucosal spray. It has been suggested that CBD attenuates THC-induced tachycardia, anxiety, and euphoria. In this study, pharmacodynamic effects were compared over 10.5 h in nine cannabis smokers randomly assigned to receive placebo, 5 and 15 mg oral synthetic THC, and low (5.4 mg THC, 5.0 mg CBD) and high (16.2 mg THC, 15.0 mg CBD) doses of Sativex. ⋯ Oral THC and Sativex produced similar, clinically insignificant increases in heart rate, anxiety, and "good drug effects" with no serious adverse events. Oral and oromucosal THC have slower absorption, lower rate of THC delivery to the brain, and fewer associated adverse events as compared with smoked cannabis. These results indicate that Sativex has a pharmacodynamic safety profile comparable to that of oral THC at low, therapeutic doses.
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Clin. Pharmacol. Ther. · Mar 2011
The missing association: sequencing-based discovery of novel SNPs in VKORC1 and CYP2C9 that affect warfarin dose in African Americans.
It is well recognized that the genetic variants VKORC1-1639, CYP2C9*2, and CYP2C9*3 contribute to warfarin dose response. This has led to warfarin dosing algorithms that include these polymorphisms and explains between 47% and 56% of variability in dose in Caucasians. However, these polymorphisms explain significantly less of the variance in dose among African Americans. ⋯ Through ethnicity-specific warfarin dose model building in 330 African Americans, we identified two novel genetic associations with higher warfarin dose, namely, VKORC1-8191 (rs61162043, P = 0.0041) and 18786 in CYP2C9 (rs7089580, P = 0.035). These novel finds are independent of the previous associations with these genes. Our regression model, encompassing both genetic and clinical variables, explained 40% of the variability in warfarin dose in African-American subjects, significantly more than any model thus far.