Organic anion-transporting polypeptides (OATP) 1B1 and 1B3 are widely acknowledged as important and rate-limiting to the hepatic
uptake of many drugs in clinical use. Accordingly, to better ...understand the in vivo relevance of OATP1B transporters, targeted
disruption of murine Slco1b2 gene was carried out. It is noteworthy that Slco1b2 (-/-) mice were fertile, developed normally, and exhibited no overt phenotypic abnormalities. We confirmed the loss of Oatp1b2
expression in liver using real-time polymerase chain reaction, Western Blot analysis, and immunohistochemistry. Expression
of Oatp1a4 and Oatp2b1 but not Oatp1a1 was greater in female Slco1b2 (-/-) mice, but expression of other non-OATP transporters did not significantly differ between wild-type and Slco1b2 (-/-) male mice. Total bilirubin level was elevated by 2-fold in the Slco1b2 (-/-) mice despite the fact that liver enzymes ALT and AST were normal. Pharmacological characterization was carried out using
two prototypical substrates of human OATP1B1 and -1B3, rifampin and pravastatin. After a single intravenous dose of rifampin
(1 mg/kg), a 1.7-fold increase in plasma area under the concentration-time curve (AUC) was observed, whereas the liver-to-plasma
ratio was reduced by 5-fold, and nearly 8-fold when assessed at steady-state conditions after 24 h of continuous subcutaneous
infusion in Slco1b2 (-/-) mice. Likewise, continuous subcutaneous infusion at low (8 μg/h) or high (32 μg/h) dose rates of pravastatin resulted
in a 4-fold lower liver-plasma ratio in the in Slco1b2 (-/-) mice. This is the first report of altered drug disposition profile in the Slco1b2 knockout mice and suggests the utility of this model for understanding the in vivo role of hepatic OATP transporters in drug
disposition.
Changes in gastric pH can impact the dissolution and absorption of compounds presenting pH-dependent solubility. We assessed, in dogs, the effects of gastric pH-modifying agents on the oral ...absorption of two weakly basic anticancer drugs, dasatinib and GDC-0941. We also tested whether drug-induced hypochlorhydria could be temporarily mitigated using betaine HCl. Pretreatments with pentagastrin, famotidine, betaine HCl, or combinations of famotidine and betaine HCl were administered orally to dogs prior to drug dosing. The gastric pH was measured under each condition for up to 7 h, and the exposure of the compounds tested was calculated. The average gastric pH in fasted dogs ranged from 1.45 to 3.03. Pentagastrin or betaine HCl treatments lowered the pH and reduced its variability between dogs compared to control animals. In contrast, famotidine treatment maintained gastric pH at values close to 7 for up to 5 h, while betaine HCl transiently reduced the pH to approximately 2 in the famotidine-treated dogs. Famotidine pretreatment lowered GDC-0941 exposure by 5-fold, and decreased dasatinib measurable concentrations 30-fold, compared to the pentagastrin-treated dogs. Betaine HCl restored GDC-0941 AUC in famotidine-treated dogs to levels achieved in control animals, and increased dasatinib AUC to 1.5-fold that measured in control dogs. The results confirmed the negative impact of acid-reducing agents on the absorption of weakly basic drugs. They also suggested that betaine HCl coadministration may be a viable strategy in humans treated with acid-reducing agents in order to temporarily reduce gastric pH and restore drug exposure.
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IJS, KILJ, NUK, PNG, UL, UM
33.
Pharmacogenomics in the age of personalized medicine Dickmann, Leslie J.; Ware, Joseph A.
Drug discovery today. Technologies,
September-December 2016, 2016 Sep - Dec, 2016-09-00, 20160901, Volume:
21-22
Journal Article
Peer reviewed
The aim of personalized medicine is to offer the right treatment to the right person at the right dose, thus maximizing efficacy and minimizing toxicity for each individual patient. Pharmacogenomic ...approaches attempt to refine the aim of personalized medicine by utilizing an individual's germline and somatic DNA signatures to guide treatment. In this review, we highlight the current use of pharmacogenomic based biomarker information in drug labeling. We also present several case studies on the implementation of pharmacogenomic strategies in drug discovery and development. Lastly, we comment on current challenges to implementing pharmacogenomic based testing in the clinic.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Totally percutaneous aortic aneurysm repair has been shown to be technically feasible, with low morbidity. Complications from percutaneous arterial closure are not insignificant, however, and can be ...fatal. We sought to evaluate our experience with this technique, compare it with the published literature, and identify factors associated with conversion to open repair and complications.
A retrospective review of a prospectively collected database was performed. All patients who underwent percutaneous closure of large-bore-sheath (>12F) access sites with off-label use of a suture-mediated closure device (Prostar XL) between December 2002 and August 2005 were reviewed. Outcome measures evaluated were rates of technical success, conversion to open femoral arterial repair, and complications. Axial diameter measurements of the accessed vessels were assessed with computed tomographic (CT) angiography both before and after the procedure. Patient variables were compared by using χ
2, Fisher exact, and paired and independent samples
t tests where appropriate. The mean follow-up interval was 1.5 years.
During the study period, 49 patients underwent percutaneous closure of 79 large-bore-sheath access sites after successful endovascular aneurysm repair. Seven patients (14%) were morbidly obese (body mass index >35 kg/m
2). Successful closure was achieved in 74 access sites (93.7%). Percutaneous closure was unsuccessful in five access sites (6.3%), all of which required open femoral repair at the same setting. Two converted patients experienced complications (4.1%): one retroperitoneal hematoma requiring transfusion of blood products and one iliac artery injury leading to death from myocardial infarction. Both of these patients were morbidly obese. Both complications occurred after closure of larger than 20F sheath sites. Morbid obesity and sheath size greater than 20F were associated with a significantly increased complication rate (
P = .02 and
P = .01, respectively). No thrombotic or infectious complications occurred in this series. Upon comparison of preoperative and postoperative CT angiograms, one (1.3%) small pseudoaneurysm was detected. No arteriovenous fistulas or hematomas larger than 3 cm were detected. The pseudoaneurysm occurred after closure of a 20F sheath access site. There were no significant differences in minimum intraluminal (7.38 ± 1.8 vs 7.48 ± 1.8) or maximum extraluminal (11.25 ± 2.8 vs 12.02 ± 2.7) diameters between preoperative and postoperative CT angiograms, respectively.
Totally percutaneous aortic aneurysm repair is technically feasible in most cases, with no effect on the luminal diameter of the accessed femoral artery. Complications occur more often in morbidly obese patients and with sheaths larger than 20F. These complications can be minimized with meticulous technique and good patient selection. The capability for expeditious open femoral arterial repair is mandatory with this approach.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Acalabrutinib is a Bruton tyrosine kinase (BTK) inhibitor approved to treat adults with chronic lymphocytic leukemia, small lymphocytic lymphoma, or previously treated mantle cell lymphoma. As the ...bioavailability of the acalabrutinib capsule (AC) depends on gastric pH for solubility and is impaired by acid‐suppressing therapies, coadministration with proton‐pump inhibitors (PPIs) is not recommended. Three studies in healthy subjects (N = 30, N = 66, N = 20) evaluated the pharmacokinetics (PKs), pharmacodynamics (PDs), safety, and tolerability of acalabrutinib maleate tablet (AT) formulated with pH‐independent release. Subjects were administered AT or AC (orally, fasted state), AT in a fed state, or AT in the presence of a PPI, and AT or AC via nasogastric (NG) route. Acalabrutinib exposures (geometric mean % coefficient of variation, CV) were comparable for AT versus AC (AUCinf 567.8 ng h/mL 36.9 vs 572.2 ng h/mL 38.2, Cmax 537.2 ng/mL 42.6 vs 535.7 ng/mL 58.4, respectively); similar results were observed for acalabrutinib's active metabolite (ACP‐5862) and for AT‐NG versus AC‐NG. The geometric mean Cmax for acalabrutinib was lower when AT was administered in the fed versus the fasted state (Cmax 255.6 ng/mL %CV, 46.5 vs 504.9 ng/mL 49.9); AUCs were similar. For AT + PPI, geometric mean Cmax was lower (371.9 ng/mL %CV, 81.4 vs 504.9 ng/mL 49.9) and AUCinf was higher (AUCinf 694.1 ng h/mL 39.7 vs 559.5 ng h/mL 34.6) than AT alone. AT and AC were similar in BTK occupancy. Most adverse events were mild with no new safety concerns. Acalabrutinib formulations were comparable and AT could be coadministered with PPIs, food, or via NG tube without affecting the PKs or PDs.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Many orally administered, small-molecule, targeted anticancer drugs, such as dasatinib, exhibit pH-dependent solubility and reduced drug exposure when given with acid-reducing agents. We previously ...demonstrated that betaine hydrochloride (BHCl) can transiently re-acidify gastric pH in healthy volunteers with drug-induced hypochlorhydria. In this randomized, single-dose, three-way crossover study, healthy volunteers received dasatinib (100 mg) alone, after pretreatment with rabeprazole, and with 1500 mg BHCl after rabeprazole pretreatment, to determine if BHCl can enhance dasatinib absorption in hypochlorhydric conditions. Rabeprazole (20 mg b.i.d.) significantly reduced dasatinib C
max
and AUC
0-∞
by 92 and 78%, respectively. However, coadministration of BHCl significantly increased dasatinib C
max
and AUC
0-∞
by 15- and 6.7-fold, restoring them to 105 and 121%, respectively, of the control (dasatinib alone). Therefore, BHCl reversed the impact of hypochlorhydria on dasatinib drug exposure and may be an effective strategy to mitigate potential drug-drug interactions for drugs that exhibit pH-dependent solubility and are administered orally under hypochlorhydric conditions.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
GDC-0941 is an orally administered potent, selective pan-inhibitor of phosphatidylinositol 3-kinases (PI3Ks) with good preclinical antitumor activity in xenograft models and favorable ...pharmacokinetics and tolerability in phase 1 trials, and it is currently being investigated in phase II clinical trials as an anti-cancer agent. In vitro solubility and dissolution studies suggested that GDC-0941, a weak base, displays significant pH-dependent solubility. Moreover, preclinical studies conducted in famotidine-induced hypochlorhydric dog suggested that the pharmacokinetics of GDC-0941 may be sensitive to pharmacologically induced hypochlorhydria. To investigate the clinical significance of food and pH-dependent solubility on GDC-0941 pharmacokinetics a four-period, two-sequence, open-label, randomized, crossover study was conducted in healthy volunteers. During the fasting state, GDC-0941 was rapidly absorbed with a median T max of 2 h. The presence of a high-fat meal delayed the absorption of GDC-0941, with a median T max of 4 h and a modest increase in AUC relative to the fasted state, with an estimated geometric mean ratio (GMR, 90% CI) of fed/fasted of 1.28 (1.08, 1.51) for AUC0–∞ and 0.87 (0.70, 1.06) for C max. The effect of rabeprazole (model PPI) coadministration on the pharmacokinetics of GDC-0941 was evaluated in the fasted and fed state. When comparing the effect of rabeprazole + GDC-0941 (fasted) to baseline GDC-0941 absorption in a fasted state, GDC-0941 median T max was unchanged, however, both C max and AUC0–∞ decreased significantly after pretreatment with rabeprazole, with an estimated GMR (90% CI) of 0.31 (0.21, 0.46) and 0.46 (0.35, 0.61), respectively for both parameters. When rabeprazole was administered in the presence of the high-fat meal, the impact of food did not fully reverse the pH effect; the overall effect of rabeprazole on AUC0–∞ was somewhat attenuated by the high-fat meal (estimate GMR of 0.57, with 90% CI, 0.50, 0.65) but unchanged for the C max (estimate of 0.43, with 90% CI, 0.37, 0.50). The results of the current investigations emphasize the complex nature of physicochemical interactions and the importance of gastric acid for the dissolution and solubilization processes of GDC-0941. Given these findings, dosing of GDC-0941 in clinical trials was not constrained relative to fasted/fed states, but the concomitant use of ARAs was restricted. Mitigation strategies to limit the influence of pH on exposure of molecularly targeted agents such as GDC-0941 with pH-dependent solubility are discussed.
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The placenta plays an important role in modulating xenobiotic passage from mother to fetus. Studies in mice have demonstrated that placental ABCB1 and ABCG2 can affect the transfer of drugs across ...the placental barrier, suggesting a role for these transporters in protecting the fetus from environmental toxicants or drugs ingested by the mother during pregnancy. To assess the role of these transporters in the human placenta, studies were conducted to evaluate the expression and functional activity of placental ABCB1 and ABCG2. The effect of maternal smoking on these placental transporters was also assessed. Uptake rates of 3Hvinblastine and 3Hmitoxantrone were used to measure ABCB1 and ABCG2 activity, respectively, and CYP1A1 activity was assessed using ethoxyresorufin O-deethylation as a positive control for smoking-related enzyme induction. ABCB1 and ABCG2 expression levels were measured by immunoblotting techniques. ATP-dependent uptake of 3Hvinblastine in vesicles was osmotically sensitive, suggesting intravesicular accumulation, and was inhibited by verapamil, an ABCB1 inhibitor. ATP-dependent uptake of 3Hmitoxantrone was inhibited by fumitremorgin C, an ABCG2 inhibitor, but not by verapamil, suggesting that the uptake of 3Hmitoxantrone was primarily mediated by ABCG2. Although CYP1A1 activity was greatly induced in smokers, no statistical differences (p > 0.05) were noted in ABCB1 and ABCG2 activity or expression between smokers and nonsmokers. In summary, both ABCB1 and ABCG2 are expressed at high levels in human placenta and are functionally active, suggesting a protective role with respect to fetal exposure to xenobiotics ingested by the mother.
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