ABSTRACT
Initiation of warfarin therapy using trial-and-error dosing is problematic. Our goal was to develop and validate a pharmacogenetic algorithm. In the derivation cohort of 1,015 participants, the independent predictors of therapeutic dose were: VKORC1 polymorphism -1639/3673 G>A (-28% per allele), body surface area (BSA) (+11% per 0.25 m(2)), CYP2C9(*)3 (-33% per allele), CYP2C9(*)2 (-19% per allele), age (-7% per decade), target international normalized ratio (INR) (+11% per 0.5 unit increase), amiodarone use (-22%), smoker status (+10%), race (-9%), and current thrombosis (+7%). This pharmacogenetic equation explained 53-54% of the variability in the warfarin dose in the derivation and validation (N= 292) cohorts. For comparison, a clinical equation explained only 17-22% of the dose variability (P < 0.001). In the validation cohort, we prospectively used the pharmacogenetic-dosing algorithm in patients initiating warfarin therapy, two of whom had a major hemorrhage. To facilitate use of these pharmacogenetic and clinical algorithms, we developed a nonprofit website, http://www.WarfarinDosing.org.
Subject(s)
Anticoagulants/administration & dosage , Aryl Hydrocarbon Hydroxylases/genetics , Mixed Function Oxygenases/genetics , Pharmacogenetics , Warfarin/administration & dosage , Aged , Algorithms , Anticoagulants/adverse effects , Anticoagulants/metabolism , Cohort Studies , Cytochrome P-450 CYP2C9 , Dose-Response Relationship, Drug , Female , Hemorrhage/chemically induced , Humans , Male , Middle Aged , Polymorphism, Genetic , Predictive Value of Tests , Vitamin K Epoxide Reductases , Warfarin/adverse effects , Warfarin/metabolismABSTRACT
Our objective was to determine if beta(1)-adrenergic receptor (beta(1)-AR) and beta(2)-AR gene polymorphisms influence heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) response to dobutamine during dobutamine stress echocardiography (DSE). Patients (n=163) undergoing clinically indicated DSE were enrolled. Dobutamine doses were titrated from 5 to 40 microg kg(-1) min(-1) at 3 min intervals and HR, SBP and DBP were measured. Genotypes were determined for beta(1)-AR Ser49Gly, beta(1)-AR Arg389Gly, beta(2)-AR Arg16Gly and beta(2)-AR Gln27Glu polymorphisms by polymerase chain reaction-restriction fragment length polymorphism analysis, pyrosequencing and single primer extension methods. beta(2)-AR Glu27 homozygotes had a greater HR response at the highest dobutamine dose than Gln27 carriers (P=0.002). Beta(2)-AR Gly16 homozygotes had a lower HR response during 5-30 microg kg(-1) min(-1) of the dobutamine infusion protocol compared to Arg16 carriers (P=0.03). Differences in SBP by beta(2)-AR codon 16 genotype and DBP by beta(1)-AR codon 389 genotype were found at baseline and were maintained throughout DSE (P=0.06 and 0.02, respectively). However, the magnitude of SBP and DBP response to dobutamine did not differ significantly by beta(2)-AR codon 16 or beta(1)-AR codon 389 genotypes, respectively. These data suggest that the four selected beta(1)- and beta(2)-AR polymorphisms do not substantially influence the magnitude of hemodynamic response to dobutamine during DSE.
Subject(s)
Blood Pressure/drug effects , Dobutamine/administration & dosage , Echocardiography/methods , Heart Rate/drug effects , Polymorphism, Genetic , Receptors, Adrenergic, beta/genetics , Aged , Cohort Studies , Dobutamine/pharmacology , Female , Genotype , Humans , Male , Middle AgedABSTRACT
We determined the effects of lopinavir/ritonavir on tenofovir renal clearance. Human immunodeficiency virus-infected subjects taking tenofovir disoproxil fumarate (TDF) were matched on age, race, and gender and were enrolled into one of the following two groups: group 1: subjects taking TDF plus lopinavir/ritonavir plus other nucleoside reverse transcriptase inhibitors (NRTIs); group 2: subjects taking TDF plus NRTIs and/or non-NRTIs but no protease inhibitors. Twenty-four-hour blood and urine collections were carried out in subjects for tenofovir quantification. Drug transporter genotype associations with tenofovir pharmacokinetics were examined. In 30 subjects, median (range) tenofovir apparent oral clearance, renal clearance, and fraction excreted in urine were 34.6 l/h (20.6-89.5), 11.3 l/h (6.2-22.6), and 0.33 (0.23-0.5), respectively. After adjusting for renal function, tenofovir renal clearance was 17.5% slower (P=0.04) in subjects taking lopinavir/ritonavir versus those not taking a protease inhibitor, consistent with a renal interaction between these drugs. Future studies should clarify the exact mechanism and whether there is an increased risk of nephrotoxicity.
Subject(s)
Adenine/analogs & derivatives , HIV Infections/drug therapy , HIV Protease Inhibitors/pharmacology , Kidney/drug effects , Organophosphonates/pharmacokinetics , Pyrimidinones/pharmacology , Reverse Transcriptase Inhibitors/pharmacokinetics , Ritonavir/pharmacology , Adenine/administration & dosage , Adenine/pharmacokinetics , Adenine/urine , Administration, Oral , Adult , Antiretroviral Therapy, Highly Active , Case-Control Studies , Drug Interactions , Female , Genotype , HIV Infections/genetics , HIV Infections/metabolism , HIV Protease Inhibitors/administration & dosage , Humans , Kidney/metabolism , Lopinavir , Male , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Middle Aged , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/genetics , Multidrug Resistance-Associated Proteins/metabolism , Organic Anion Transport Protein 1/genetics , Organic Anion Transport Protein 1/metabolism , Organophosphonates/administration & dosage , Organophosphonates/urine , Pyrimidinones/administration & dosage , Reverse Transcriptase Inhibitors/administration & dosage , Reverse Transcriptase Inhibitors/urine , Ritonavir/administration & dosage , Tenofovir , Treatment OutcomeABSTRACT
The objective of this study was to determine whether chronic morphine exposure increased P-glycoprotein in rat brain. Male Sprague-Dawley rats were treated with morphine, saline, or dexamethasone for 5 days. On day 6, antinociceptive effect was measured to evaluate the extent of functional tolerance to morphine. Brain P-glycoprotein was detected by Western blot analysis of whole brain homogenate. Morphine- and dexamethasone-treated rats exhibited decreased antinociceptive response when compared to saline-treated controls. Brain P-glycoprotein was approximately 2-fold higher in morphine-treated rats compared to saline controls based on Western blot analysis. Chronic morphine exposure appears to increase P-glycoprotein in rat brain. P-glycoprotein induction may enhance morphine efflux from the brain, thus reducing morphine's pharmacologic activity. Induction of P-glycoprotein may be one mechanism involved in the development of morphine tolerance.
