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Bilirubin has antioxidant and anti-inflammatory properties in vitro and in animal studies and protects against inflammatory, cardiovascular, and other diseases in observational studies; therefore, bilirubin has potential as a therapeutic agent. However, observational studies could be confounded by many factors. We used a genetic (n = 61,281) and clinical (n = 234,670) approach to define the association between bilirubin and 19 conditions with a putative protective signal in observational studies. We also tested if individuals with genetically higher bilirubin levels underwent more diagnostic tests. We used a common variant in UGT1A1 (rs6742078) associated with an 26% increase in bilirubin levels in the genetic studies. Carriers of the variant had higher bilirubin levels (P = 2.2 × 10-16 ) but there was no significant association with any of the 19 conditions. In a phenome-wide association study (pheWAS) to seek undiscovered genetic associations, the only significant finding was increased risk of "jaundice-not of newborn." Carriers of the variant allele were more likely to undergo an abdominal ultrasound (odds ratio = 1.04, [1.00-1.08], P = 0.03). In contrast, clinically measured bilirubin levels were significantly associated with 15 of the 19 conditions (P

Post-marketing population pharmacokinetic (PK) and pharmacodynamic (PD) studies can be useful to capture patient characteristics affecting PK or PD in real-world settings. These studies require longitudinally measured dose, outcomes, and covariates in large numbers of patients; however, prospective data collection is cost-prohibitive. Electronic health records (EHRs) can be an excellent source for such data, but there are challenges, including accurate ascertainment of drug dose. We developed a standardized system to prepare datasets from EHRs for population PK/PD studies. Our system handles a variety of tasks involving data extraction from clinical text using a natural language processing algorithm, data processing, and data building. Applying this system, we performed a fentanyl population PK analysis, resulting in comparable parameter estimates to a prior study. This new system makes the EHR data extraction and preparation process more efficient and accurate, and provides a powerful tool to facilitate post-marketing population PK/PD studies using information available in EHRs.

Tizanidine, a widely used muscle relaxant that can lower blood pressure, is metabolized by the cytochrome P450 1A2 (CYP1A2). We studied 1,626 patients prescribed tizanidine and 5,012 prescribed cyclobenzaprine concurrently with a strong CYP1A2 inhibitor. The primary outcome was severe hypotension, defined as systolic blood pressure (SBP) ≤ 70 mmHg during periods of drug co-exposure. Severe hypotension occurred more often in the tizanidine group (2.03%; n = 33) than the cyclobenzaprine group (1.28%; n = 64); odds ratio (OR) = 1.60; P = 0.029. This difference remained statistically significant after adjustment for a log-transformed propensity score that included age, sex, race, Charlson's comorbidity index, and concurrent use of antihypertensive medications (OR = 1.57; P = 0.049). A sensitivity analysis that defined hypotension as SBP < 90 mmHg also yielded higher rates of hypotension among patients prescribed tizanidine. In conclusion, CYP1A2 inhibition increases the risk of hypotensive episodes associated with the use of tizanidine in routine clinical practice.

Background and Objectives The α2A-adrenergic receptor (ADRA2A) plays a central role in the regulation of systemic sympathetic activity and hence cardiovascular responses such as heart rate and blood pressure. The objectives of this study were to systematically search for variants in the ADRA2A gene, to define the gene's haplotype structure, and to examine potential functional effects of these variants. Methods We examined 5957 base pairs of contiguous sequence of ADRA2A (promoter, exonic, and 3′-flanking region) using polymerase chain reaction to amplify the genomic target, followed by bidirectional sequencing, in 135 healthy subjects (85 white and 50 black subjects). Haplotypes were inferred by use of an expectation-maximization algorithm. Primary (plasma norepinephrine concentration) and secondary (resting heart rate and blood pressure) phenotypes were compared among subjects grouped by individual polymorphisms and haplotypes. Results We identified 41 variants, including 24 novel variants. On the basis of 9 optimally selected markers, 11 haplotypes in 5 haplotype groups were inferred, representing approximately 99% of the cohort. Two uncommon variants in complete linkage disequilibrium (G>C at −1903 and C>G at −1607, identified in 3 black subjects) were associated with significantly increased plasma norepinephrine concentrations (376.7 ± 6.1 pg/mL versus 218.4 ± 95.0 pg/mL, P = .011). There was no other significant association between genetic variants or any of the haplotypes with phenotypes. Conclusion We describe novel variants and the haplotype structure of the ADRA2A gene. Common genetic ADRA2A variants are not important determinants of baseline cardiovascular measures (plasma norepinephrine, heart rate, and blood pressure) in healthy volunteers. Clinical Pharmacology & Therapeutics (2006) 79, 173–185; doi: 10.1016/j.clpt.2005.10.006

Objective The α1A-adrenergic receptor is highly expressed in human vasculature including resistance arteries and veins, and its stimulation is primarily responsible for adrenergically mediated smooth muscle contraction. Variability in sensitivity to phenylephrine, an α1A adrenergic agonist, has a large genetic component. We examined the hypothesis that a common polymorphism of α1A-adrenergic receptor (Arg347Cys) affects in vivo response. Methods We measured vascular sensitivity to phenylephrine using the dorsal hand vein linear variable differential transformer technique and determined α1A-adrenergic receptor genotype in 74 healthy, nonsmoking adults (28 Arg/Arg, 30 Arg/Cys, and 16 Cys/Cys). Results Sensitivity to phenylephrine, expressed as the dose of phenylephrine resulting in 50% venoconstriction (Phe50), was not significantly different in subjects with the 3 α1A adrenergic receptor genotypes: Phe50 geometric mean (95% confidence interval) was 513 ng/min (287–9–8 ng/min) for Arg/Arg, 431 ng/min (274–680 ng/min) for Arg/Cys, and 471 ng/min (197–1124 ng/min) for Cys/Cys (P = .90). Conclusion We conclude that the Arg347Cys receptor polymorphism does not alter agonist-mediated venoconstriction in vivo. Clinical Pharmacology & Therapeutics (2004) 75, 539–545; doi: 10.1016/j.clpt.2004.02.006

Background Sildenafil, a treatment for erectile dysfunction, is a specific phosphodiesterase type 5 (PDE 5) inhibitor that enhances nitric oxide (NO)–mediated vasodilation in the corpus cavernosum by inhibiting cyclic guanosine monophosphate breakdown. Since PDE 5 is widely expressed in the vasculature, we examined the hypothesis that sildenafil could enhance NO-mediated vasodilation in other vascular beds and improve endothelial function. Methods NO-mediated responses to acetylcholine (endothelium-dependent) and nitroglycerin (endothelium-independent) were measured in healthy men in the dorsal hand vein (n = 13), after the administration of either sildenafil 50 mg or placebo. Flow-mediated dilation of the brachial artery and forearm postischemic reactive hyperemia were measured before and after sildenafil 50 mg, isosorbide dinitrate 5 mg, and placebo in a double-blind, randomized, crossover study (n = 11). Results In the hand vein, sildenafil administration increased sensitivity to local nitroglycerin. The 50% effective dose decreased approximately 4-fold from 13.5 ng/min (range, 6.9–26.6 ng/min) to 2.7 ng/min (range, 1.1–6.4 ng/min) (P = .025). Sildenafil decreased the maximum venoconstriction induced by phenylephrine from 81% ± 3% to 74% ± 3% (P = .025). Sildenafil did not significantly affect the maximal venodilatory response to acetylcholine (35% ± 7% after placebo versus 32% ± 8% after sildenafil) (P = .7). In the arterial vasculature, flow-mediated dilation before (2.4% ± 1%) and after (2.8% ± 1.4%) sildenafil (P = .8) and postischemic reactive hyperemia area under the curve before (1807 ± 393 mL · min · s/100 mL) and after (1467 ± 257 mL · min · s/100 mL) sildenafil were not different (P = .8). Resting heart rate, blood pressure, and resting brachial artery diameter were unchanged after sildenafil administration. Isosorbide dinitrate, an endothelium-independent vasodilator, caused a significant increase in resting brachial artery diameter from 0.53 ± 0.01 cm to 0.56 ± 0.02 cm (P = .005), without altering flow-mediated dilation. Conclusions In healthy men sildenafil increased sensitivity to nitroglycerin, an exogenous NO donor, approximately 4-fold but did not affect endothelium-dependent, NO-mediated responses in either the hand vein or forearm vasculature. Differential vascular responses to sildenafil may localize its enhancement of endogenous NO-mediated vasodilation to vascular beds such as the corpus cavernosum. Clinical Pharmacology & Therapeutics (2001) 70, 270–279; doi: 10.1067/mcp.2001.117995

Background Renal allograft survival is lower in African American patients compared with white patients. Interethnic differences in cyclosporine (INN, ciclosporin) pharmacokinetics in renal transplant recipients have been described but have not been well characterized. Pharmacodynamic responses to cyclosporine have not been compared among ethnic groups. Methods Healthy men were studied after 5 days on a controlled diet. Cyclosporine concentrations were determined in whole blood drawn at intervals over 24 hours after administration of a microemulsion cyclosporine formulation (4 mg/kg; 9 African American subjects and 9 white subjects) and after a standard cyclosporine formulation (4 mg/kg; 10 African American subjects and 10 white subjects). Inhibition of phytohemagglutinin-P–stimulated interleukin-2 production in whole blood drawn 4 hours after cyclosporine was used as a pharmacodynamic measure to compare the effect of cyclosporine in African American and white subjects. Results The microemulsion cyclosporine formulation (area under the cyclosporine concentration-time curve, 7432 ± 560 ng · h/mL in African American subjects and 7043 ± 454 ng · h/mL in white subjects) was more bioavailable than the standard formulation (area under the cyclosporine concentration-time curve, 4828 ± 319 ng · h/mL in African American subjects and 4538 ± 301 ng · h/mL in white subjects); this resulted in an approximately 50% greater area under the cyclosporine concentration-time curve (P < .001 in both ethnic groups). There were no differences between African American subjects and white subjects in any pharmacokinetic measurement, with both the standard and the microemulsion cyclosporine formulations. Inhibition of phytohemagglutinin-P–stimulated interleukin-2 production 4 hours after the administration of cyclosporine was similar in African American subjects (70% ± 5% inhibition) and white subjects (64% ± 7% inhibition; P = .5). Conclusions The pharmacokinetics and pharmacodynamics of cyclosporine were similar in a matched group of African American and white subjects studied under controlled conditions. Environmental factors may contribute more than genetic variability to the lower bioavailability of cyclosporine reported in African American renal transplant recipients. Clinical Pharmacology & Therapeutics (2001) 69, 317–323; doi: 10.1067/mcp.2001.115073

Background and Objectives The most common polymorphisms of the human β2-adrenergic receptor-Arg16Gly and Gln27Glu-are associated with alterations in β2-adrenergic receptor responses, both in vitro and in vivo. β2-Adrenergic receptor–mediated vascular responses are affected by ethnicity, blood pressure, and genotype. We tested the hypothesis that these two common β2-adrenergic receptor genetic variants are associated with essential hypertension in black or white Americans. Subjects and Methods In a population-based case-control association study, the relationship between β2-adrenergic receptor genotypes and hypertension was examined in 307 normotensive subjects (128 black and 179 white) and 356 hypertensive subjects (155 black and 201 white). A polymerase chain reaction–based single-stranded conformational polymorphism method with direct sequencing of the bands of interest was used to detect the two frequently occurring β2-adrenergic receptor variants (Arg16Gly, Gln27Glu). Results No significant differences in the distributions of alleles and genotypes of the tested β2-adrenergic receptor variants were found between normotensive and hypertensive groups from either black or white Americans (all P > .05). There was a marked interethnic difference in the frequency of the Gln27Glu β2-adrenergic receptor polymorphism in both normotensive and hypertensive subjects. In normotensive white subjects, the variant Glu27 allele (35.2% versus 18.0%; P < .0001) and Glu27 homozygous genotype (14.0% versus 4.7%; P < .01) were more common than in black subjects. Similarly, in hypertensive white subjects, the variant Glu27 allele (35.8% versus 18.4%; P < .0001) and the Glu27 homozygous genotype (15.9% versus 2.6%; P < .0001) were more common than in black subjects. Conclusions These data suggest that although there are marked ethnic differences in their distribution, the common genetic polymorphisms of the human β2-adrenergic receptor gene do not cosegregate with the presence of hypertension in either black or white Americans. Clinical Pharmacology & Therapeutics (2000) 67, 670–675; doi: 10.1067/mcp.2000.106293

Background Attenuated vasodilation in response to the intra-arterial administration of the β-adrenergic agonist isoproterenol (INN, isoprenaline), an endothelium-independent vasodilator, has previously been observed in normotensive black Americans. To determine whether this reflected a more generalized attenuation of responses to vasodilators, we compared forearm blood flow responses to the endothelium-dependent vasodilator methacholine and the endothelium-independent vasodilator sodium nitroprusside in young normotensive black men and white men. Methods Forearm blood flow responses to the intra-arterial administration of isoproterenol (10 to 400 ng/min), methacholine (0.25 to 8 μg/min), and sodium nitroprusside (0.25 to 8 μg/min) were measured with use of venous occlusion plethysmography in 11 normotensive black men (mean ± SE age, 30.5 ± 2.2 years) and nine normotensive white men (mean age, 28.0 ± 3.2 years). Results Baseline characteristics, including baseline forearm blood flow, were similar in the black and the white subjects. Vasodilation in response to isoproterenol, sodium nitroprusside, and methacholine was significantly attenuated in black subjects, resulting respectively in a 3.7-fold, 3.6-fold, and 5.0-fold increase in forearm blood flow in black subjects and a 7.5-fold, 5.2-fold, and 6.9-fold increase in forearm blood flow in white subjects (ANOVA; isoproterenol, p < 0.0001; sodium nitroprusside, p < 0.0001; methacholine, p = 0.01). Conclusions Our finding of attenuated nitric oxide-mediated vasodilation in response to methacholine and sodium nitroprusside in healthy black American men suggests that attenuated vasodilation in black subjects is a relatively generalized phenomenon, resulting in attenuated responses to multiple vasodilators that act through different receptor- and nonreceptor-mediated mechanisms. Clinical Pharmacology & Therapeutics (1997) 62, 436–443; doi

Introduction Cytochrome P4503A (CYP3A) is primarily responsible for the metabolism of cyclosporine and that of many other drugs. Several substrates of CYP3A have been investigated for use as pharmacologic probes to predict the CYP3A-metabolizing capacity of an individual and, therefore, the disposition of other CYP3A substrate drugs. One such measure of CYP3A activity is the 14C erythromycin breath test, which has been applied to the prediction of cyclosporine disposition. However, the test has practical limitations. Because of this, the 0- to-8-hour urinary dapsone recovery ratio has been studied as an alternative and more practical probe of CYP3A activity. Methods The dapsone recovery ratio and the 14C erythromycin breath test were correlated with cyclosporine concentrations in 16 patients with rheumatoid arthritis to determine the usefulness of the dapsone recovery ratio as an alternative to the 14C erythromycin breath test. The erythromycin breath test showed a fourfold variation between subjects and correlated weakly with trough cyclosporine concentrations (r = −0.50, P < 0.05), whereas the dapsone recovery ratio varied only approximately twofold between subjects and did not correlate with trough cyclosporine concentrations (r = 0.02, p = 0.94). The correlation between the dapsone recovery ratio and the erythromycin breath test (r = 0.22, p = 0.41) was not significant. Conclusions These data suggest that results obtained with one probe in vivo may not apply to another CYP3A substrate. The poor quantitative relationship between cyclosporine concentrations and the erythromycin breath test limits its usefulness in the prediction of an individual's cyclosporine dose requirement Clinical Pharmacology & Therapeutics (1996) 59, 47–51; doi

Elevated C-reactive protein (CRP), homocysteine and inflammatory cytokines such as interleukin-6 (IL-6) are associated with increased cardiovascular risk. CRP has direct inflammatory actions stimulating the production of IL-6 and monocyte chemoattactant protein-1, (MCP-1) in whole blood. Homocysteine increases the production of MCP-1 and IL-8 in endothelial cellsin vitro, but whether it has direct inflammatory actions in an environment more representative of in vivo biology, is not known. Thus, we examined the hypothesis that homocysteine would stimulate the production of IL-6 and MCP-1 in whole blood. Blood was drawn from 15 healthy subjects and incubated with saline, 1μg/ml lipopolysaccaride (LPS), 50 (n=8) and 100 μM/L (n=6) DL-homocysteine or 5 μg/ml human recombinant CRP for 24 hours. Both CRP and LPS significantly increased the production of IL-6 and MCP-1 more than 4-fold (P