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1.  The association of adiposity with kidney function decline among HIV-infected adults: Findings from the FRAM (Fat Redistribution and Metabolic Changes in HIV Infection) Study 
HIV medicine  2014;16(3):184-190.
To study the association of adiposity with longitudinal kidney function change in 544 HIV-infected persons in Study of Fat Redistribution and Metabolic Change in HIV infection (FRAM) cohort over 5 years of follow-up.
Regional distribution of muscle and adipose tissue was quantified by whole-body MRI, and total adiponectin and leptin levels were measured in serum. Kidney function was assessed by estimated glomerular filtration rate from serum cystatin C (eGFRCys), obtained at baseline and follow-up. Rapid kidney function decline was defined as annual loss of eGFRCys ≥ 3 ml/min/1.73m2, and incident chronic kidney disease (CKD) was defined at eGFRCys < 60 ml/min/1.73m2. Multivariate regression analysis was adjusted for age, race, gender, glucose, antihypertensive use, serum albumin, baseline and change in HIV viral load.
At baseline, mean age was 43 years, mean eGFRCys 86 ml/min/1.73m2, and 21% had albuminuria. Mean (standard deviation) eGFRCys decline was −0.11 ± 4.87 ml/min/1.73m2 per year; 23% of participants had rapid kidney function decline, and 10% developed incident CKD. Lowest tertile of visceral adipose tissue and highest tertile of adiponectin were both marginally associated with annual kidney function decline of −0.5 ml/min/1.73m2 each, but these associations were not statistically significant after adjustment. We found no statistically significant associations of MRI-measured regional adiposity or serum adipokines with rapid kidney function decline or incident CKD (all p-values > 0.1 in adjusted models).
Contrary to findings in the general population, adiposity did not have a substantial association with longitudinal change in kidney function among HIV-infected persons.
PMCID: PMC4320665  PMID: 25251910
adiposity; FRAM; HIV; kidney decline
2.  Influence of CYP2C8*2 on the pharmacokinetics of pioglitazone in healthy African American volunteers 
Pharmacotherapy  2013;33(9):1000-1007.
Study Objectives
To determine the influence of the CYP2C8*2 polymorphism on pioglitazone pharmacokinetics in healthy African American volunteers.
Prospective, open-label, single-dose pharmacokinetic study.
University of Colorado Hospital Clinical and Translational Research Center.
Healthy African-American volunteers between 21 to 60 years of age were enrolled in the study based on CYP2C8 genotype: CYP2C8*1/*1 (n=9), CYP2C8*1/*2 (n=7), and CYP2C8*2/*2 (n=1).
Participants received a single 15 mg dose of pioglitazone in the fasted state, followed by a 48-hour pharmacokinetic study.
Measurements and Main Results
Plasma concentrations of pioglitazone and its M-III (keto) and M-IV (hydroxy) metabolites were compared between participants with the CYP2C8*1/*1 genotype and CYP2C8*2 carriers. Pioglitazone AUC0-∞ and t1/2 did not differ significantly between CYP2C8*1/*1 and CYP2C8*2 carriers (AUC0-∞,7331 ± 2846 versus 10431 ± 5090 ng*h/ml, p=0.15; t1/2, 7.4 ± 2.7 versus 10.5 ± 4.0 h, p=0.07). M-III and M-IV AUC0-48 also did not differ significantly between genotype groups. However, the M-III/pioglitazone AUC0-48 ratio was significantly lower in CYP2C8*2 carriers than CYP2C8*1 homozygotes (0.70 ± 0.15 versus 1.2 ± 0.37, p=0.006). Similarly, CYP2C8*2 carriers had a significantly lower M-III/M-IV AUC0-48 ratio than participants with the CYP2C8*1/*1 genotype (0.82 ­± 0.26 versus 1.22 ± 0.26, p=0.006).
These data suggest that CYP2C8*2 influences pioglitazone pharmacokinetics in vivo, particularly the AUC0-48 ratio of M-III to parent drug, and the AUC0-48 ratio of M-III to M-IV. Additional, larger studies are needed to further investigate the impact of CYP2C8*2 on the pharmacokinetics of CYP2C8 substrates in individuals of African descent.
PMCID: PMC3760990  PMID: 23712614
pioglitazone; CYP; CYP2C8; pharmacokinetics; pharmacogenetics; African-American
3.  Effect of ABCB1 polymorphisms and atorvastatin on sitagliptin pharmacokinetics in healthy volunteers 
The objectives of this study were to determine if ABCB1 polymorphisms are associated with interindividual variability in sitagliptin pharmacokinetics, and if atorvastatin alters the pharmacokinetic disposition of sitagliptin in healthy volunteers.
In this open-label, randomized, two-phase crossover study, healthy volunteers were prospectively stratified according to ABCB1 1236/2677/3435 diplotype (n=9, CGC/CGC; n=10, CGC/TTT; and n=10, TTT/TTT). In one phase, participants received a single 100 mg dose of sitagliptin. In the other phase, participants received 40 mg of atorvastatin for five days, with a single 100 mg dose of sitagliptin administered on day 5. A 24 hour pharmacokinetic study followed each sitagliptin dose, and the study phases were separated by a 14-day washout period.
Sitagliptin pharmacokinetic parameters did not differ significantly between ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotype groups during the monotherapy phase. Atorvastatin administration did not significantly affect sitagliptin pharmacokinetics, with GMRs (90% CIs) for sitagliptin Cmax, AUC0-∞, CLR, and fe of 0.93 (0.86, 1.01), 0.96 (0.91, 1.01), 1.02 (0.93, 1.12), and 0.98 (0.90, 1.06), respectively.
ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotypes did not influence sitagliptin pharmacokinetics in healthy volunteers. Furthermore, atorvastatin had no effect on the pharmacokinetics of sitagliptin in the setting of ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotypes.
PMCID: PMC3676426  PMID: 23407853
sitagliptin; atorvastatin; ABCB1; P-glycoprotein; pharmacogenetic; pharmacokinetic
4.  Changes in Fat Mitochondrial DNA and Function in Subjects Randomized to Abacavir-Lamivudine or Tenofovir DF–Emtricitabine With Atazanavir-Ritonavir or Efavirenz: AIDS Clinical Trials Group Study A5224s, Substudy of A5202 
The Journal of Infectious Diseases  2012;207(4):604-611.
Background. The effect of nonthymidine nucleoside reverse-transcriptase inhibitors (NRTIs) on fat mitochondrial DNA (mtDNA) content and function is unclear.
Methods. A5202 randomized antiretroviral therapy–naive human immunodeficiency virus–infected subjects to abacavir-lamivudine (ABC/3TC) versus tenofovir DF–emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir-ritonavir (ATV/r). A5224s, substudy of A5202, enrolled 269 subjects with fat measurements by dual-energy x-ray absorptiometry and computed tomography. A subset of subjects underwent fat biopsies at baseline and week 96 for mtDNA content (real-time polymerase chain reaction) and oxidative phosphorylation nicotinamide adenine dinucleotide (reduced) dehydrogenase (complex I) and cytochrome c oxidase (complex IV) activity levels (immunoassays). Intent-to-treat analyses were performed using analysis of variance and paired t tests.
Results. Fifty-six subjects (87% male; median age, 39 years) were included; their median body mass index, CD4 cell count, and fat mtDNA level were 26 kg/m2, 227 cells/μL, and 1197 copies/cell, respectively. Fat mtDNA content decreased within the ABC/3TC and TDF/FTC groups (combining EFV and ATV/r arms; median change, −341 [interquartile range, −848 to 190; P = .03] and −400 [−661 to −221; P < .001] copies/cell, respectively), but these changes did not differ significantly between the 2 groups (P = .57). Complex I and IV activity decreased significantly in the TDF/FTC group (median change, −12.45 [interquartile range, −24.70 to 2.90; P = .003] and −8.25 [−13.90 to −1.30; P < .001], optical density × 103/µg, respectively) but not the ABC/3TC group. Differences between the ABC/3TC and TDF/FTC groups were significant for complex I (P = .03).
Conclusions. ABC/3TC and TDF/FTC significantly and similarly decreased fat mtDNA content, but only TDF/FTC decreased complex I and complex IV activity levels.
Clinical Trials Registration. NCT00118898.
PMCID: PMC3549598  PMID: 23204164
lipoatrophy; lipodystrophy; metabolic disease; mitochondrial dysfunction; mitochondrial toxicity; oxidative phosphorylation
5.  Evaluation of the relationship between circulating omentin-1 concentrations and components of the metabolic syndrome in adults without type 2 diabetes or cardiovascular disease 
Dysregulation of omentin-1, a beneficial adipokine, is thought to play a role in the development of type 2 diabetes and cardiovascular disease. The objective of this study was to evaluate the relationship between circulating omentin-1 concentrations and components of the metabolic syndrome in adults without type 2 diabetes or cardiovascular disease, and to determine if sex differences influenced the observed relationships.
Fasting blood samples were obtained from 93 adults, ages 30–60 years, without type 2 diabetes and/or cardiovascular disease. Participants were classified as having the metabolic syndrome according to American Heart Association/National Heart, Lung and Blood Institute criteria. Plasma omentin-1 concentrations were measured using a commercially-available enzyme-linked immunosorbent assay, and relationships between plasma omentin-1 and components of the metabolic syndrome were assessed in the entire study cohort, by metabolic syndrome status, and by sex.
On average, participants were 48 ± 8 years of age, 50.5% were women, 54.8% were Caucasian, and 70% had the metabolic syndrome. Plasma omentin-1 concentrations did not differ significantly between individuals with versus without the metabolic syndrome (145.7 ± 70 versus 157.4 ± 79.3 ng/ml, p = 0.50). However, men with the metabolic syndrome had significantly lower omentin-1 levels than men without the metabolic syndrome (129.9 ± 66 versus 186.3 ± 84.3 ng/ml, p = 0.03). Plasma omentin-1 concentrations were significantly correlated with HDL cholesterol in the entire study cohort (r = 0.26; p = 0.01), which was primarily driven by a correlation in men (r = 0.451, p = 0.002) and participants with the metabolic syndrome (r = 0.36; p = 0.003). Plasma omentin-1 concentrations did not differ significantly between men and women; however men with the metabolic syndrome had 20% lower plasma omentin-1 levels than women with the metabolic syndrome (p = 0.06).
These data demonstrate that circulating omentin-1 levels are associated with HDL cholesterol, primarily in men and in the presence of the metabolic syndrome. In addition, sex appears to influence the relationship between plasma omentin-1 concentrations and components of the metabolic syndrome. Additional studies are needed to explore sexual dimorphism in circulating omentin-1 levels, and the role of omentin-1 in the metabolic syndrome.
PMCID: PMC3901757  PMID: 24428913
Omentin-1; Metabolic syndrome; Adipokine; Sexual dimorphism
6.  Impact of the CYP2C8 *3 polymorphism on the drug–drug interaction between gemfibrozil and pioglitazone 
The objective of this study was to determine the extent to which the CYP2C8*3 allele influences pharmacokinetic variability in the drug–drug interaction between gemfibrozil (CYP2C8 inhibitor) and pioglitazone (CYP2C8 substrate).
In this randomized, two phase crossover study, 30 healthy Caucasian subjects were enrolled based on CYP2C8*3 genotype (n = 15, CYP2C8*1/*1; n = 15, CYP2C8*3 carriers). Subjects received a single 15 mg dose of pioglitazone or gemfibrozil 600 mg every 12 h for 4 days with a single 15 mg dose of pioglitazone administered on the morning of day 3. A 48 h pharmacokinetic study followed each pioglitazone dose and the study phases were separated by a 14 day washout period.
Gemfibrozil significantly increased mean pioglitazone AUC(0,∞) by 4.3-fold (P < 0.001) and there was interindividual variability in the magnitude of this interaction (range, 1.8- to 12.1-fold). When pioglitazone was administered alone, the mean AUC(0,∞) was 29.7% lower (P= 0.01) in CYP2C8*3 carriers compared with CYP2C8*1 homozygotes. The relative change in pioglitazone plasma exposure following gemfibrozil administration was significantly influenced by CYP2C8 genotype. Specifically, CYP2C8*3 carriers had a 5.2-fold mean increase in pioglitazone AUC(0,∞) compared with a 3.3-fold mean increase in CYP2C8*1 homozygotes (P= 0.02).
CYP2C8*3 is associated with decreased pioglitazone plasma exposure in vivo and significantly influences the pharmacokinetic magnitude of the gemfibrozil–pioglitazone drug-drug interaction. Additional studies are needed to evaluate the impact of CYP2C8 genetics on the pharmacokinetics of other CYP2C8-mediated drug–drug interactions.
PMCID: PMC3555061  PMID: 22625877
CYP2C8 protein human; drug interaction; gemfibrozil; pharmacogenetics; pharmacokinetics; pioglitazone
7.  Association of Increased Upper Trunk and Decreased Leg Fat With 2-h Glucose in Control and HIV-Infected Persons 
Diabetes Care  2011;34(11):2448-2453.
Changes in body fat distribution and abnormal glucose metabolism are common in HIV-infected patients. We hypothesized that HIV-infected participants would have a higher prevalence of impaired glucose tolerance (IGT) compared with control subjects.
A total of 491 HIV-infected and 187 control participants from the second examination of the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) underwent glucose tolerance testing (GTT). Multivariable regression was used to identify factors associated with GTT parameters.
The prevalence of impaired fasting glucose (IFG) (>110 mg/dL) was similar in HIV-infected and control participants (21 vs. 25%, P = 0.23). In those without IFG, the prevalence of IGT was slightly higher in HIV-infected participants compared with control subjects (13.1 vs. 8.2%, P = 0.14) and in HIV+ participants with lipoatrophy versus without (18.1 vs. 11.5%, P = 0.084). Diabetes detected by GTT was rare (HIV subjects 1.3% and control subjects 0%, P = 0.65). Mean 2-h glucose levels were 7.6 mg/dL higher in the HIV-infected participants (P = 0.012). Increased upper trunk subcutaneous adipose tissue (SAT) and decreased leg SAT were associated with 2-h glucose and IGT in both HIV-infected and control participants. Adjusting for adipose tissue reduced the estimated effects of HIV. Exercise, alcohol use, and current tenofovir use were associated with lower 2-h glucose levels in HIV-infected participants.
In HIV infection, increased upper trunk SAT and decreased leg SAT are associated with higher 2-h glucose. These body fat characteristics may identify HIV-infected patients with normal fasting glucose but nonetheless at increased risk for diabetes.
PMCID: PMC3198295  PMID: 21926283
8.  Uridine supplementation in the treatment of HIV lipoatrophy: Results of ACTG 5229 
AIDS (London, England)  2010;24(16):2507-2515.
Lipoatrophy is prevalent on thymidine NRTIs (tNRTI). A pilot trial showed that uridine (NucleomaxX®) increased limb fat.
A5229 was a multicenter trial in which HIV-infected individuals with lipoatrophy on tNRTI-regimens were randomized to NucleomaxX or placebo. Primary endpoint was change in limb fat from baseline to week-48. The study was powered to detect 400-gram difference between arms at week-48. A stratified Wilcoxon rank-sum test was used to assess between-arm differences.
The 165 subjects were 91% male, 62% white; median age 49 years, CD4 506 cells/mm3, and limb fat 3037 grams; 81% had HIV-1 RNA ≤50 copies/mL; 76% were on AZT. Baseline characteristics were similar between groups. Only 59% completed 48-weeks of treatment, however only 3 subjects (1 on uridine) discontinued due to toxicity (diarrhea). In intent-to-treat, there was no difference for changes in limb fat between treatments at week-24 or week-48. On as-treated analysis, uridine resulted in an increase in %limb fat vs. placebo (3.4% vs. −0.8%, p=0.01) at week-24 but not at week-48 (1.8% vs.3.8%, p=0.93). Similar results were seen when limiting the analysis to subjects with ≥80% adherence. The results were not related to severity of lipoatrophy or type of tNRTI. No changes were found in facial-anthropometrics, fasting lipids, trunk-fat, CD4, or HIV-RNA.
We found a modest transient improvement in limb fat after 24 weeks of uridine. The lack of sustained efficacy at week-48 was not due to changes in adherence or reduction in sample size. Uridine was safe and did not impair virologic control.
PMCID: PMC2956768  PMID: 20827170
9.  Influence of SLCO1B1 and CYP2C8 gene polymorphisms on rosiglitazone pharmacokinetics in healthy volunteers 
Human Genomics  2008;3(1):7-16.
Polymorphisms in drug transporter genes and/or drug-metabolising enzyme genes may contribute to inter-individual variability in rosiglitazone pharmacokinetics in humans. We sought to determine the joint effects of polymorphisms in the SLCO1B1 drug transporter gene and the cytochrome P450 (CYP) 2C8-metabolising enzyme gene on rosiglitazone pharmacokinetics in healthy volunteers. Healthy Caucasian subjects were prospectively enrolled on the basis of SLCO1B1 521 T > C genotype. Additionally, subjects were genotyped for SLCO1B1 11187 G > A, - 10499 A > C and 388 A > G polymorphisms, and the CYP2C8*3 polymorphism. SLCO1B1 haplotypes and diplotypes were computationally assigned. Rosiglitazone plasma concentrations were determined by high-performance liquid chromatography and analysed using non-compartmental methods. The study population consisted of 26 subjects, with a mean age of 33 ± 9 years, and a mean weight of 66.6 ± 11.7 kg. There were no significant differences in rosiglitazone pharmacokinetic parameters between SLCO1B1 diplotype groups. Subjects with the CYP2C8*1/*3 genotype (n = 7), however, had significantly lower rosiglitazone area under the plasma concentration-time curve (AUC) and significantly higher rosiglitazone oral clearance, compared with CYP2C8 wild-type homozygotes (n = 19). Stepwise linear regression analysis revealed that CYP2C8 genotype (p = 0.006) and weight (p = 0.022) were significant predictors of rosiglitazone AUC (overall p = 0.002; R2 = 41.6 per cent). We concluded that polymorphisms in the CYP2C8 drug-metabolising enzyme gene, but not the SLCO1B1 drug transporter gene, significantly influence rosiglitazone disposition in humans. Future studies examining the influence of CYP2C8 genotypes and haplotypes on thiazolidinedione disposition and response in patients with type 2 diabetes are warranted.
PMCID: PMC3525178  PMID: 19129086
rosiglitazone; thiazolidinedione; pharmacokinetic; pharmacogenetic; CYP2C8; SLCO1B1

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