Laropiprant (LRPT), a prostaglandin D
2
receptor‐1 antagonist shown to reduce niacin‐induced flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This open‐label, ...randomized, 2‐period crossover study assessed the pharmacokinetics of single‐dose rosiglitazone in the presence and absence of multiple‐dose LRPT. Twelve healthy male and female subjects, 34–64 years of age, received two, once‐daily oral treatments in random sequence separated by ≥3‐day washout: (1) multiple‐dose LRPT 40 mg/day for 7 days (Days 1 to 7) coadministered with single‐dose rosiglitazone 4 mg on Day 6; (2) single‐dose rosiglitazone 4 mg on Day 1. Comparability was declared because the 90% confidence interval (CI) for the AUC
0‐∞
geometric mean ratio (GMR; rosiglitazone + LRPT/rosiglitazone alone) 0.92 (0.86, 0.99), was contained within prespecified bounds (0.70, 1.43). The
C
max
GMR (90% CI) for rosiglitazone was 0.98 (0.95, 1.02). There was no evidence of clinically meaningful alterations in the pharmacokinetics of rosiglitazone, a probe CYP2C8 substrate, following coadministration of multiple‐dose LRPT in healthy subjects. Therefore, findings suggest that LRPT does not inhibit CYP2C8‐mediated metabolism.
Rolofylline is a potent, selective adenosine A1 receptor antagonist that was under development for the treatment of patients with acute decompensated heart failure and renal function impairment. This ...was a phase I, randomized, open-label, 2-period, fixed-sequence study in 19 healthy adult volunteers to examine the effect of multiple intravenous rolofylline doses on the single-dose pharmacokinetics of midazolam, a sensitive CYP3A4 substrate. In period 1, subjects received a single oral dose of midazolam 7.5 mg on day 1. In period 2, subjects received 30 mg, 4-hour infusions of rolofylline (intended clinical dose and duration) once daily for 4 consecutive days; midazolam 7.5 mg was coadministered on day 4. The geometric mean ratios and 90% confidence intervals for AUC0-infinity and Cmax of midazolam in the presence/absence of rolofylline were 1.20 (1.12-1.29) and 1.17 (1.03-1.32), respectively. The apparent terminal half-life (t1/2) for midazolam was similar in the presence/absence of rolofylline (4.31 and 4.27 hours, respectively). The geometric mean ratios (90% confidence intervals) for AUC0-infinity and Cmax of 1'-hydroxymidazolam in the presence/absence of rolofylline were 1.04 (0.96-1.13) and 0.98 (0.84-1.14), respectively. The t1/2 for 1'-hydroxymidazolam was slightly higher in the presence relative to absence of rolofylline (4.24 and 3.17 hours, respectively). Multiple doses of intravenous rolofylline 30 mg for 4 days were generally well tolerated and did not result in clinically important inhibition of CYP3A4 as indicated by little or no change in the pharmacokinetics of midazolam.
Laropiprant (LRPT), a prostaglandin D2 receptor 1 antagonist shown to reduce niacin-induced flushing symptoms, is being developed in combination with niacin for the treatment of dyslipidemia. This ...study assessed the pharmacokinetics/pharmacodynamics of single-dose warfarin in the presence/absence of multiple-dose LRPT. Thirteen subjects received 2 treatments in random order separated by > or =10-day washout: (1) multiple-dose LRPT 40 mg/d for 12 days (days -5 to 7) with coadministered single-dose warfarin 30 mg (day 6) and (2) single-dose warfarin 30 mg (day 1). R+- and S(-)-warfarin and international normalized ratio (INR) were assayed predose and up to 168 hours postdose. Comparability was declared if the 90% confidence intervals (CIs) for the geometric mean ratio (GMR; warfarin + LRPT/warfarin alone) of area under the plasma concentration curve from zero to infinity (AUC0-infinity) for R+- and S(-)-warfarin were contained within (0.80, 1.25). The estimated GMRs of AUC0-infinity (90% CIs) were 1.02 (0.96, 1.09) and 1.04 (0.98, 1.09) for R+- and S(-)-warfarin, respectively. The estimated GMRs of maximum plasma concentration (Cmax) (90% CIs) were 1.13 (1.02, 1.26) and 1.11 (0.99, 1.24) for R+- and S(-)-warfarin, respectively. The estimated GMRs of area under the prothrombin time INR curve from 0 to 168 hours on day 21 (INR AUC0-168 h) and average maximum observed prothrombin time INR (INRmax) were 1.02 (0.99, 1.05) and 1.04 (0.98, 1.10), respectively. There was no evidence of clinically meaningful alterations in the pharmacokinetics and pharmacodynamics (ie, INR) of R(+)- or S(-)-warfarin after coadministration of multiple-dose LRPT and single-dose warfarin.
Rolofylline is a potent, selective adenosine A1 receptor antagonist that was under development for the treatment of patients with acute decompensated heart failure and renal function impairment. The ...30-mg dose of rolofylline administered by intravenous infusion over 4 hours for 3 days represented the anticipated recommended clinical regimen of rolofylline. This was a randomized, double-blind, double-dummy, placebo-controlled, three-period crossover study performed with a single 2-hour intravenous infusion of 60 mg rolofylline, placebo, or oral moxifloxacin in healthy subjects. Plasma samples were collected for determination of rolofylline, M1-trans, and M1-cis pharmacokinetic parameters. The upper limit of the two-sided 90% confidence interval for the placebo-adjusted least squares mean change from baseline in QTcF interval for rolofylline was less than 5 msec at every time point. Moxifloxacin demonstrated an increase in QTcF of greater than 10 msec at 2, 2.5, and 3 hours postdose, thus establishing the sensitivity of the assay to detect modest increases in QTcF interval. Mean Cmax values of 1947.4, 739.2, and 54.8 nM were attained for rolofylline and its metabolites M1-trans and M1-cis, respectively, which were 2.2- to 3.1-fold higher than historic Cmax values seen at the anticipated clinical dose and regimen. Adenosine A1 receptor antagonism from a single supratherapeutic intravenous dose of 60 mg rolofylline over 2 hours was generally well tolerated and did not prolong the QTcF interval relative to placebo.
Hepatocyte-specific gene expression requires the interaction of many proteins with multiple binding sites in the regulatory regions. HNF-3 is a site found to be important in the maximal ...hepatocyte-specific expression of several genes. We find that liver nuclear extracts contain three major binding activities for this site, which we call HNF-3A, HNF-3B, and HNF-3C. Purification from rat liver nuclear extracts of HNF-3A and HNF-3C reveals that each activity corresponds to a distinct polypeptide, as determined by SDS-PAGE. Peptide sequence derived from the most abundant species, HNF-3A, was used for synthesizing probes with which to isolate a cDNA clone of this protein. The encoded protein contains 466 amino acids (48.7 kD) and has binding properties identical to those of the purified protein. A 160-amino-acid region that does not resemble the binding domain of any known transcription factor is essential for DNA binding. The mRNA for HNF-3A is present in the rat liver but not in brain, kidney, intestine, or spleen, and the basis for this difference is cell-specific regulation of HNF-3A gene transcription.
Hepatocyte nuclear factor (HNF)-3α, -3β, and -3γ are liver transcription factors that mediate the coordinate expression of a number of hepatocyte-specific genes. The HNF-3 proteins share ...DNA-binding-domain homology among themselves and with the Drosophila homeotic protein forkhead (fkh). The HNF-3/fkh DNA-binding domain constitutes an uncharacterized protein motif that recognizes its cognate DNA binding site as a monomer. Additional HNF-3/fkh-related proteins are known to be required for determination events during embryogenesis in Drosophila and Xenopus. In this report, we describe the isolation of nine additional HNF-3/fkh homologue (HFH) clones from rodent tissue cDNAs by using both low-stringency hybridization and a polymerase chain reaction protocol. Many of the HFH genes exhibit a tissue-restricted expression pattern and are transcribed in tissues other than liver, including brain, kidney, lung, and intestine. The HNF-3/fkh motif therefore comprises a large gene family of transcription factors that play a role in tissue-specific gene regulation and development.
Laropiprant is a prostaglandin D2 receptor 1 antagonist that is being developed in combination with niacin for the treatment of dyslipidemia. This randomized clinical study evaluated the effect of ...laropiprant on the pharmacokinetics of ethinyl estradiol (EE) and norelgestromin (NGMN), the principal circulating metabolite of norgestimate, in healthy women receiving 3 or more months of an oral contraceptive (Ortho Tri-Cyclen; Ortho-McNeil Pharmaceutical, Raritan, NJ), which contains EE and norgestimate. Twenty-one female subjects with normal menstrual cycles received the oral contraceptive on Days 1 to 21 during two consecutive contraceptive cycles. Subjects received double-blind 40 mg/day laropiprant or placebo on Days 1 to 21 of each contraceptive cycle. Plasma samples were collected predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose on Day 21 to measure area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24hr) and maximum concentration observed in plasma (Cmax) of EE and NGMN. Comparability would be declared if the 90% confidence intervals for the geometric mean ratio of AUC0-24hr and Cmax in the absence and presence of laropiprant were within predefined bounds (0.80-1.25). The estimated geometric mean ratios (90% confidence intervals) of EE and NGMN, respectively, were 1.08 (1.04-1.13) and 0.97 (0.94-0.99) for AUC0-24hr and 1.16 (1.06-1.27) and 1.00 (0.94-1.06) for Cmax. The 90% confidence intervals for the geometric mean ratio of EE Cmax minimally exceeded the prespecified bounds; the other relevant pharmacokinetic parameters fell within the predefined bounds. Coadministration of 40 mg laropiprant with the oral contraceptive did not lead to clinically meaningful alterations in the pharmacokinetics of EE or NGMN.
The unique phenotype of each differentiated cell in an animal (or plant) arises from selective expression of genes in a cell- or tissue-specific fashion, which is controlled primarily at the level of ...transcription. This review will focus on transcription factors that regulate cell-specific transcription in one intensely studied cell type, the hepatocyte or parenchymal liver cell. All of the recently isolated transcription factors that are important in hepatocyte-specific gene expression were identified in adult liver and there are strong hints that some of these may play an important role in embryogenesis.
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