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ABSTRACT: HMG-CoA reductase inhibitors (statins) are contraindicated during pregnancy. However, it has been suggested that the hydrophilic property of pravastatin prevents its placental transfer to the fetus, explaining neutral effects observed in controlled studies. Using the ex-vivo placental perfusion model, placental transfer of pravastatin (50 ng/ml) was determined. The mean maximum fetal concentration was 4.4 ng/ml. The transfer of pravastatin's across the placenta appears to be limited and slow. Combined with its rapid elimination half-life of 2 h and 50% protein binding, the transfer of pravastatin from maternal to fetal compartments is substantially more limited than observed in the perfusion experiments.
Placenta 06/2013; · 3.69 Impact Factor
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ABSTRACT: Drug transporters are now widely acknowledged as important determinants governing drug absorption, excretion, and, in many cases, extent of drug entry into target organs. There is also a greater appreciation that altered drug transporter function, whether due to genetic polymorphisms, drug-drug interactions, or environmental factors such as dietary constituents, can result in unexpected toxicity. Such effects are in part due to the interplay between various uptake and efflux transporters with overlapping functional capabilities that can manifest as marked interindividual variability in drug disposition in vivo. Here we review transporters of the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies considered to be of major importance in drug therapy and outline how understanding the expression, function, and genetic variation in such drug transporters will result in better strategies for optimal drug design and tissue targeting as well as reduce the risk for drug-drug interactions and adverse...
01/2012; 52:249-273.
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ABSTRACT: Response to statin therapy is often unpredictable because of variability in metabolism and transport. In the recently created organic anion transporting-polypeptide 1b2 (Oatp1b2/Slco1b2)-null mice, the investigators found significantly lower liver-to-plasma ratios compared with controls for atorvastatin (16.0 ± 5.1 vs 43.5 ± 13.7, P = .002) and rosuvastatin (15.2 ± 3.3 vs 28.4 ± 9.3, P = .03), but not simvastatin (5.2 ± 1.1 vs 6.3 ± 2.9, P = .49), following tail vein injection of 1 mg/kg of each drug. In addition, the investigators examined intraindividual variation in atorvastatin, rosuvastatin, and simvastatin pharmacokinetics in healthy human subjects in a crossover study design. Areas under the plasma concentration-time curve of atorvastatin and simvastatin acid were significantly related (Spearman r = 0.68; P = .035), whereas rosuvastatin profile was not related to atorvastatin or simvastatin exposure. Together, these results in mice and humans demonstrate that predictability of exposure to one statin based on another is dependent on the specific statin pairs and the context in which they are compared.
The Journal of Clinical Pharmacology 12/2011; · 2.91 Impact Factor
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K Eechoute,
R M Franke,
W J Loos,
L A Scherkenbach,
I Boere,
J Verweij,
H Gurney, R B Kim,
R G Tirona,
R H J Mathijssen,
A Sparreboom
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ABSTRACT: The bioavailability of orally administered imatinib is >90%, although the drug is monocationic under the acidic conditions in the duodenum. In vitro, we found that imatinib is transported by the intestinal uptake carrier organic anion transporting polypeptide (OATP1A2) and that this process is sensitive to pH, rosuvastatin, and genetic variants. However, in a study in patients with cancer, imatinib absorption was not associated with OATP1A2 variants and was unaffected by rosuvastatin. These findings highlight the importance of verifying in a clinical setting the drug-transporter interactions observed in in vitro tests.
Clinical Pharmacology & Therapeutics 06/2011; 89(6):816-20. · 6.04 Impact Factor
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ABSTRACT: Mesna and its dimer, dimesna, are coadministered for mitigation of ifosfamide- and cisplatin-induced toxicities, respectively. Dimesna is selectively reduced to mesna in the kidney, producing its protective effects. In vitro screens of uptake and efflux transporters revealed saturable uptake by renal organic anion transporters OAT1, OAT3, and OAT4. Efflux transporters breast cancer resistance protein; multidrug and toxin extrusion 1 (MATE1); multidrug resistance proteins MRP1, MRP2, MRP4, and MRP5; and P-glycoprotein (Pgp) significantly reduced dimesna accumulation. Further investigation demonstrated that renal apical efflux transporters MATE1, MRP2, and Pgp were also capable of mesna efflux. Administration of OAT inhibitor probenecid to healthy subjects significantly increased combined mesna and dimesna plasma exposure (91% ± 34%) while decreasing the renal clearance due to net secretion (67.0% ± 12.7%) and steady-state volume of distribution (45.2% ± 13.4%). Thus, the kidney represents a significant sink of total mesna, whereas function of renal drug transporters facilitates clearance in excess of glomerular filtration rate and likely the presence of active mesna in the urine. Loss of renal transporter function due to genetic variability or drug-drug interactions may decrease the efficacy of chemoprotectants, increasing the risk of ifosfamide- and cisplatin-induced toxicities.
The Journal of Clinical Pharmacology 04/2011; 52(4):530-42. · 2.91 Impact Factor
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Clinical Pharmacology & Therapeutics 02/2011; 89(4):612-6. · 6.04 Impact Factor
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ABSTRACT: Drug transporters are now widely acknowledged as important determinants governing drug absorption, excretion, and, in many cases, extent of drug entry into target organs. There is also a greater appreciation that altered drug transporter function, whether due to genetic polymorphisms, drug-drug interactions, or environmental factors such as dietary constituents, can result in unexpected toxicity. Such effects are in part due to the interplay between various uptake and efflux transporters with overlapping functional capabilities that can manifest as marked interindividual variability in drug disposition in vivo. Here we review transporters of the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies considered to be of major importance in drug therapy and outline how understanding the expression, function, and genetic variation in such drug transporters will result in better strategies for optimal drug design and tissue targeting as well as reduce the risk for drug-drug interactions and adverse drug responses.
Annual Review of Pharmacology 01/2011; 52:249-73. · 21.64 Impact Factor
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ABSTRACT: St John's wort (SJW) is known to induce cytochrome P450 (CYP) 3A4 and P-glycoprotein through pregnane X-receptor activation. Our study evaluated the effects of long-term SJW administration on oral and intravenous pharmacokinetics of the nonmetabolized in vivo probe of P-glycoprotein, talinolol, in relation to intestinal P-glycoprotein expression. In a controlled, randomized study (N=9), the pharmacokinetics of oral (50 mg) and intravenous talinolol (30 mg) was determined before and after 12 days SJW (900 mg daily, Jarsin 300). Duodenal biopsies were taken and MDR1 genotypes assessed. SJW reduced the oral talinolol bioavailability by 25% (P=0.049) compared with water control. A 93% increase in oral clearance (P=0.177) and a 31% reduction in area under the serum concentration time curve (AUC; P=0.030) were observed. Renal and nonrenal clearance (CLNR), elimination half-life, peak serum drug concentration (Cmax), and time to reach Cmax were not significantly altered. After intravenous talinolol, SJW affected only CLNR (35% increase compared with water, P=0.006). SJW increased MDR1 messenger ribonucleic acid (mRNA) as well as P-glycoprotein levels in the duodenal mucosa. Subjects with the combined MDR1 genotype comprising 1236C>T, 2677G>T/A, and 3435C>T polymorphisms had lower intestinal MDR1 mRNA levels and displayed an attenuated inductive response to SJW as assessed by talinolol disposition. Long-term SJW decreased talinolol AUC with a corresponding increase in intestinal MDR1 expression, suggesting that SJW has a major inductive effect on intestinal P-glycoprotein. Interestingly, the magnitude of induction appeared to be affected by MDR1 genotype.
Clinical Pharmacology & Therapeutics 05/2007; 81(5):669-78. · 6.04 Impact Factor
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ABSTRACT: We showed previously that grapefruit and orange juices inhibited human enteric organic anion-transporting polypeptide (OATP)1A2 in vitro and lowered oral fexofenadine bioavailability clinically. Inhibition of OATP1A2 transport by flavonoids in grapefruit (naringin) and orange (hesperidin) was conducted in vitro. Two randomized, crossover, pharmacokinetic studies were performed clinically. In one study, 120 mg of fexofenadine was ingested with 300 ml grapefruit juice, an aqueous solution of naringin at the same juice concentration (1,200 microM), or water. In the other study, fexofenadine was administered with grapefruit juice, with or 2 h before aqueous suspension of the particulate fraction of juice containing known clinical inhibitors of enteric CYP3A4, but relatively low naringin concentration (34 microM), or with water. Naringin and hesperidin's half-maximal inhibitions were 3.6 and 2.7 microM, respectively. Fexofenadine area under the plasma drug concentration-time curves (AUCs) with grapefruit juice and naringin solution were 55% (P<0.001) and 75% (P<0.05) of that with water, respectively. Fexofenadine AUCs with grapefruit juice and particulate fractions were 57% (P<0.001), 96% (not significant (NS)), and 97% (NS) of that with water, respectively. Individuals tested in both studies (n=9 of 12) had highly reproducible fexofenadine AUC with water (r(2)=0.85, P<0.001) and extent of reduction of it with grapefruit juice (r(2)=0.72, P<0.01). Naringin most probably directly inhibited enteric OATP1A2 to decrease oral fexofenadine bioavailability. Inactivation of enteric CYP3A4 was probably not involved. Naringin appears to have sufficient safety, specificity, and sensitivity to be a clinical OATP1A2 inhibitor probe. Inherent OATP1A2 activity may be influenced by genetic factors. This appears to be the first report of a single dietary constituent clinically modulating drug transport.
Clinical Pharmacology & Therapeutics 05/2007; 81(4):495-502. · 6.04 Impact Factor
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H Glaeser,
D G Bailey,
G K Dresser,
J C Gregor,
U I Schwarz,
J S McGrath,
E Jolicoeur,
W Lee,
B F Leake,
R G Tirona, R B Kim
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ABSTRACT: The goals of this study were to assess the extent of human intestinal drug transporter expression, determine the subcellular localization of the drug uptake transporter OATP1A2, and then to assess the effect of grapefruit juice consumption on OATP1A2 expression relative to cytochrome P450 3A4 and MDR1. Expression of drug uptake and efflux transporters was assessed using human duodenal biopsy samples. Fexofenadine uptake by different transporters was measured in a transporter-transfected cell line. We investigated the influence of grapefruit juice on pharmacokinetics of orally administered fexofenadine. The effect of grapefruit juice on the expression of intestinal transporters was determined using real-time polymerase chain reaction and Western blot analysis. In the duodenum of healthy volunteers, an array of CYP enzymes as well as uptake and efflux transporters was expressed. Importantly, uptake transporters thought to be liver-specific, such as OATP1B1 and 1B3, as well as OATP2B1 and 1A2 were expressed in the intestine. However, among OATP transporters, only OATP1A2 was capable of fexofenadine uptake when assessed in vitro. OATP1A2 colocalized with MDR1 to the brush border domain of enterocytes. Consumption of grapefruit juice concomitantly or 2 h before fexofenadine administration was associated with reduced oral fexofenadine plasma exposure, whereas intestinal expression of either OATP1A2 or MDR1 remained unaffected. In conclusion, an array of drug uptake and efflux transporters are expressed in the human intestine. OATP1A2 is likely the key intestinal uptake transporter for fexofenadine absorption whose inhibition results in the grapefruit juice effect. Although short-term grapefruit juice ingestion was associated with reduced fexofenadine availability, OATP1A2 or MDR1 expression was unaffected.
Clinical Pharmacology & Therapeutics 04/2007; 81(3):362-70. · 6.04 Impact Factor
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ABSTRACT: Background/aims: Folic acid (FA) supplementation can increase the metabolism of phenytoin and warfarin, both of which are CYP2C9 substrates, but the mechanisms underlying this are unknown. This study examined the hypothesis that FA affects transactivation of a defined core promoter in human CYP2C9 gene, in which CAR, PXR, HNF1, and HNF4 binding sites exist.Methods: CYP2C9-luciferase reporter constructs (-3kb) were transfected into HepG2 cells, and human CAR, PXR, HNF1, and HNF4 were co-transfected either alone or in combination. The transfected cells were treated with or without FA (100M), and the cells co-transfected with PXR were simultaneously treated with rifampin (Rif, 10M), followed by dual luciferase assays. Data were expressed as fold activation versus vector control.Results: Compared with each of the vehicle controls, FA treatment did not significantly affect luciferase activities (FA vs DMSO: 1.9 0.6 vs 1.8 0.6 for CAR; 12.9 4.2 vs 12.5 3.8 for CAR+ HNF1; 14.9 7.8 vs 15.4 9.3 for CAR+ HNF4; 1.3 0.3 vs 1.3 0.4 for PXR/Rif; 9.4 2.8 vs 8.9 2.6 for PXR/Rif+ HNF1; 3.1 1.5 vs 3.1 1.8 for PXR/Rif+ HNF4; all P> 0.05, n = 6 each).Conclusions: In transfected HepG2 cells, acute administration of folic acid has no effect on CYP2C9 transcriptional activity, regardless of co-transfection with CAR, PXR, HNF1, and HNF4, alone or in combination. The effect of folic acid on the metabolism of CYP2C9 substrates is not mediated by alteration of transcription by key nuclear receptors.
Clinical Pharmacology & Therapeutics 01/2006; 79(2):P15-P15. · 6.04 Impact Factor
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ABSTRACT: Background/aims: Patients with HNF1 gene mutations exhibit marked hypersensitivity to hypoglycemic drugs (CYP2C9 substrates). Rif-induced CYP2C9 gene expression is reduced by pretreatment with chenodeoxycholic acid, which induces expression of SHP-1. SHP-1 can repress HNF1 gene through the suppression of HNF4 and HNF4 synergistically activates PXR/Rif induction of CYP2C9. This study examined the hypothesis that HNF1 activates Rif-induced CYP2C9 transactivation and interacts with HNF4 and SHP-1.Methods: CYP2C9-luciferase reporter constructs (-3kb) were transfected into HepG2 cells, and PXR, HNF1, HNF4, SHP-1 were co-transfected individually or together. The cells were treated with or without Rif (10M), followed by dual luciferase assays. Data are expressed as fold activation versus vector control.Results: Compared with PXR/Rif alone, cells co-transfected with HNF1 or HNF4 significantly increased luciferase activity (3.6- and 4.6-fold, P < .01), but those co-transfected with both HNF1 and HNF4 only increased luciferase activity 4-fold (P < .01). As expected, SHP-1 significantly suppressed HNF4-mediated (13.9 1.9 vs 2.6 0.4, P < .05) and, to a lesser extent, HNF1-mediated (15.4 1.9 vs 9.6 1.6; P < .01) synergistic transactivation.Conclusions: HNF1 and HNF4 individually up-regulate rifampin induction of CYP2C9, but do not have additive or synergistic effects when expressed together. SHP-1 suppresses HNF1- and HNF4- mediated PXR/rifampin induction of CYP2C9.
Clinical Pharmacology & Therapeutics 01/2006; 79(2):P65-P65. · 6.04 Impact Factor
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ABSTRACT: Background/aims: The antihistaminic drug fexofenadine is frequently used as an in vivo probe of P-glycoprotein transporter function in humans. We have previously shown that OATP1A2 (OATP-A) is able to mediate the cellular uptake of fexofenadine. In this study the role of other OATPs and polymorphisms in OATP1A2 to fexofenadine uptake was assessed.Methods: We expressed an array of drug uptake transporters, including wildtype and variant OATP1A2 in HeLa cells using a recombinant vaccinia system and determined fexofenadine cellular uptake.Results: OATP1A2, but not 1B1 (OATP-C), 1B3 (OATP8) or 2B1 (OATP-B), was capable of transporting fexofenadine in expressed HeLa cells. OATP1A2*3, *5, *6, and *7 revealed significantly lower transport activity compared to OATP1A2*1. Interestingly human OCT1 showed a low but detectable transport activity for fexofenadine. In contrast to humans, multiple rat Oatps, including rat Oatp1a1, 1a4, 1a5 and 1b2 were capable of fexofenadine transport.Conclusion: Our results indicate that OATP1A2 may be an important determinant of fexofenadine disposition in humans. Furthermore, hepatic uptake of fexofenadine is likely mediated by OCT1 and not by OATP1B1 or 1B3. Since OATP1A2 is expressed in the intestine, kidney and brain, our findings suggest polymorphisms in OATP1A2 may contribute to intersubject variability in response to fexofenadine.
Clinical Pharmacology & Therapeutics 01/2006; 79(2):P20-P20. · 6.04 Impact Factor
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ABSTRACT: Background/Aim: The objective was to evaluate the effect of single and repeated grapefruit juice relative to water on oral pharmacokinetics (PK) of the non-metabolized and P-glycoprotein (Pgp)-transported drug talinolol in humans, and to assess the impact of grapefruit juice on Pgp and intestinal uptake transporters.Methods: Oral PK of 50mg talinolol was determined with water, single (300mL), and repeated grapefruit juice intake (6 days, 900mL/day) in 24 healthy Caucasians. MDR1 mRNA and Pgp levels were measured in duodenal biopsies of 3 subjects before and after juice. All subjects were genotyped for three MDR1 polymorphisms (1236C>T, 2677G>T/A, 3435C>T).Results: Single grapefruit juice decreased the talinolol AUC, Cmax, and urinary excretion values to 56% (P<.001), 57% (P<.001) and 58% (P<.001), respectively, of those with water; repeated grapefruit juice showed a 50 to 65% reduction (P<.01). Single or repeated juice intake did not affect CLR, t1/2, and tmax. MDR1 mRNA and Pgp levels in duodenal biopsies did not differ. MDR1 genotypes were not associated with altered PK of talinolol.Conclusion: Since both single and repeated juice intake lowered, rather than increased talinolol AUC without changing Pgp expression, our findings suggest constituents in grapefruit juice preferentially inhibited intestinal uptake rather than Pgp.
Clinical Pharmacology & Therapeutics 01/2005; 77(2):P4-P4. · 6.04 Impact Factor
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ABSTRACT: Rosuvastatin is an HMG-CoA reductase inhibitor (statin) used in the treatment of hypercholesterolemia. Rosuvastatin is not subject to significant metabolism; therefore its disposition is thought to be highly dependent on drug transporters expressed in organs such as the intestine, liver, and kidney. Recent studies have shown that OATP1B1 (OATP-C) can mediate the hepatic uptake of this drug. However, the extent and relevance of other OATP transporters to the disposition of this drug has not been clarified. In this study, we expressed an array of human and rat Organic Anion Transporting Polypeptide (OATP) transporters using a recombinant vaccinia system. As expected, we are able to confirm that human OATP1B1 is able to mediate the cellular uptake of rosuvastatin. In addition, human OATP1A2 (OATP-A), OATP2B1 (OATP-B), OATP1B3 (OATP-8), as well as rat Oatp1a1 (Oatp1), Oatp1a4 (Oatp2), Oatp1a5 (Oatp3), and Oatp1b2 (Oatp4) were also capable of rosuvastatin uptake. When we expressed allelic variants of human OATP1B1, profound loss of rosuvastatin uptake was noted in cells expressing *5, *9, *15, and *16 (*1b+*9) variants. Accordingly, our findings would suggest multiple OATP transporters mediate the uptake of rosuvastatin from the GI tract and liver. Moreover, involvement of other hepatic OATP transporters is likely to attenuate the impact of SLCO1B1 (OATP-C) SNPs to the overall disposition of rosuvastatin in vivo.
Clinical Pharmacology & Therapeutics 01/2005; 77(2):P64-P64. · 6.04 Impact Factor
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ABSTRACT: Organic anion transporting polypeptides (OATP) are a growing family of uptake transporters important to drug disposition. Studies from this laboratory have shown that OATP-A (SLC21A3) is selectively expressed in human intestine as well as kidney and brain. Accordingly, variability in the expression or function of this polyspecific drug uptake transporter may have important implications to bioavailability and tissue penetration of substrate drugs. In order to determine the extent of genetic heterogeneity in OATP-A, PCR-based genotyping analyses were carried out on ethnically defined genomic DNA samples (n=96 each for African-, Chinese-, European-, and Hispanic-Americans). We identified three novel nonsynonymous polymorphisms within the coding region of OATP-A; T38C (Ile38Thr), A516C (Glu172Asp) and G559A (Ala187Thr). Genotypic frequencies of these polymorphisms were dependent on race. In vitro functional assessment revealed that the A516C (Glu172Asp) variant had markedly reduced capacity for mediating the cellular uptake of OATP-A substrates, estrone sulfate and fexofenadine. Cell surface biotinylation experiments did not show altered plasma membrane expression of the transporter, suggesting the reduced transport activity associated with the A516C variant is likely due to altered intrinsic activity of the transporter. Our data suggest that OATP-A polymorphisms may contribute to inter-individual variability in intestinal absorption and CNS penetration of substrate drugs.
Clinical Pharmacology & Therapeutics 01/2004; 75(2):P93-P93. · 6.04 Impact Factor
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R B Kim
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ABSTRACT: Drug transporters are increasingly recognized as a key determinant of drug disposition. Recent studies have revealed that targeted expression of drug uptake and efflux transporters to specific cell membrane domains allows for the efficient directional movement of many drugs in clinical use. While the role of certain efflux transporters such as MDR1 (P-glycoprotein) in drug disposition has been extensively studied, emerging evidence suggests that uptake transporters may also be important to the intestinal absorption and renal or hepatic elimination of drugs. Members of the organic anion-transporting polypeptide (OATP) family of drug uptake transporters have been found capable of transporting a large array of structurally divergent drugs. Moreover, expression of OATP isoforms in the gastrointestinal tract, liver and kidney, as well as at the level of the blood-brain barrier, has important implications for our understanding of the factors governing drug absorption, elimination and tissue penetration.
European Journal of Clinical Investigation 12/2003; 33 Suppl 2:1-5. · 3.02 Impact Factor
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G G Sofowora,
V Dishy,
M Muszkat,
H G Xie, R B Kim,
P A Harris,
H C Prasad,
D W Byrne,
U B Nair,
A J J Wood,
C M Stein
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ABSTRACT: A common polymorphism of the beta(1)-adrenergic receptor Arg389Gly markedly affects function in vitro, but little is known about its in vivo significance.
Resting and exercise hemodynamic responses were measured in subjects homozygous for Arg389 (n = 21) or Gly389 (n = 13) alleles before and 3 hours after administration of a beta-blocker, atenolol. Demographic characteristics and atenolol concentrations were similar in the two genotypic groups. Genotype had a marked effect on resting hemodynamic responses to atenolol, with Arg389-homozygous subjects having a larger decrease in resting systolic blood pressure (8.7 +/- 1.3 mm Hg versus 0.2 +/- 1.7 mm Hg, P < .001) and mean arterial blood pressure (7.2 +/- 1.0 mm Hg versus 2.0 +/- 1.7 mm Hg, P = .009). Attenuation of exercise-induced hemodynamic responses by atenolol was not affected by genotype.
There is reduced sensitivity of Gly389 homozygotes to a beta-adrenergic receptor antagonist, and this polymorphism may be an important determinant of variability in response to beta-blockade.
Clinical Pharmacology & Therapeutics 04/2003; 73(4):366-71. · 6.04 Impact Factor
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ABSTRACT: Endothelial nitric oxide synthase catalyses the formation of the vasodilator nitric oxide, a major regulator of vascular tone. The Asp298 polymorphism of the nitric oxide synthase gene is associated with altered function and expression of the enzyme in vitro and myocardial infarction and coronary artery spasm in vivo. We examined the effect of the Glu298Asp polymorphism on: (1) local vascular responses to phenylephrine, acetylcholine, glyceryl trinitrate and prostaglandin E1 in the dorsal hand vein; (2) changes in forearm blood flow during mental stress, a measure of nitric oxide-mediated effect on resistance vessels; (3) excretion of urinary nitrite/nitrate as a measure of total body nitric oxide production; and (4) F2-isoprostane metabolite, a measure of oxidative stress, in healthy Glu298 (n = 12) and Asp298 (n = 13) homozygotes. There were no significant differences in acetylcholine dose responses (P = 0.29) in Glu298 and Asp298 homozygotes. Responses to glyceryl trinitrate, prostaglandin E1 and the alpha-adrenergic agonist phenylephrine did not differ by genotype. Forearm blood flow was similar at rest and increased significantly (from 7.5 ml/min/100 ml to 12.2 ml/min/100 ml; P = 0.003), but similarly (P = 0.2), during mental stress in both genotypes. Asp298 homozygotes excreted significantly less nitrate/nitrite than Glu298 homozygotes (nitrate + nitrite/creatinine ratio 0.05 +/- 0.01 vs. 0.09 +/- 0.01, respectively; P < 0.005). Urinary F2-isoprostane metabolite excretion did not differ (Glu298, 2.04 +/- 0.25 ng/mg creatinine; Asp298, 1.85 +/- 0.37 ng/mg creatinine; P = 0.7). We conclude that in healthy volunteers the Glu298Asp polymorphism affects endogenous nitric oxide production without affecting nitric oxide-mediated vascular responses. This polymorphism may only have clinical significance in the presence of endothelial dysfunction.
Pharmacogenetics 12/2001; 11(9):809-14.
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ABSTRACT: With continuous exposure to beta2-adrenergic agonists, vascular tissue becomes desensitized to agonist-mediated vasodilatation. We studied the effects of two common polymorphisms of the beta2-adrenergic receptor, one at codon 16 and one at codon 27, on agonist-mediated vasodilatation and desensitization in the vascular bed.
We studied 26 healthy subjects who were selected to represent three genotypes: 7 were homozygous for the alleles encoding Arg16 and Gln27, 8 were homozygous for the alleles encoding Gly16 and Gln27, and 11 were homozygous for the alleles encoding Gly16 and Glu27. Vascular responses were assessed by measuring changes in the diameter of a dorsal hand vein. A dose-response curve of the effect of the beta2-adrenergic-receptor agonist isoproterenol was constructed (dose range, 4 to 480 ng per minute). Desensitization was then induced by a 2-hour continuous infusion of isoproterenol, and venodilatation was measured 30, 60, 90, and 120 minutes after the start of the infusion.
Subjects who were homozygous for Arg16 had almost complete desensitization; venodilatation in response to isoproterenol in this group decreased from a mean (+/-SE) of 44+/-11 percent to 8+/-4 percent (P=0.006). In contrast, subjects who were homozygous for Gly16 did not have significant desensitization, irrespective of the amino acid encoded by codon 27. Subjects who were homozygous for Glu27 had higher maximal venodilatation in response to isoproterenol than those who were homozygous for Gln27 (86+/-13 percent vs. 54+/-8 percent, P=0.03).
The Arg16 polymorphism of the beta2-adrenergic receptor is associated with enhanced agonist-mediated desensitization in the vasculature, and the Glu27 polymorphism is associated with increased agonist-mediated responsiveness. Therefore, polymorphisms of the beta2-adrenergic receptor are potentially important determinants of the vascular response to stress.
New England Journal of Medicine 11/2001; 345(14):1030-5. · 53.30 Impact Factor
