Volume 39, No. 3/2001(March)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Viewpoint
A comprehensive account on the role of efflux transporters in the gastrointestinal absorption of 13 commonly used substrate drugs in humans
W.L. Chiou, S.M. Chung, T.C. Wu and C. Ma
Abstract
W.L. Chiou, S.M. Chung, T.C. Wu and C. Ma
Department of Pharmaceutics and Pharmacodynamics, College of Pharmacy, The University of Illinois at Chicago, USA
Background: The potential absorption-limiting effect of intestinal efflux transporters such as P-glycoprotein (P-gp) has been well recognized, primarily based on results of numerous Caco-2 cell studies showing that flux, permeability, or transport clearance of drugs from the basolateral to the apical (B à A) compartment is greater than that from the apical to the basolateral (A à B) compartment. Except for very limited examples such as celiprolol, talinolol, pafenolol and paclitaxel, the potential clinical impact of these transporters on oral absorption of the vast number of commonly prescribed drug substrates in humans has not been closely examined to date. Objective: To evaluate whether these efflux transporters may play a significant role in limiting oral absorption of 13 commonly used drugs (digoxin, etoposide, felodipine, fexofenadine, furosemide, indinavir, losartan, nadolol, propranolol, ritonavir, saquinavir, tacrolimus, and verapamil) in humans. Methods: Drug absorption properties such as the rate (as judged by the Cmax and tmax) and extent (as judged by AUC or urinary excretion of drugs) of absorption as a function of dose, as well as the completeness of oral absorption were obtained from the literature. Results: The absorption properties of these 13 drugs are not consistent with absorption-retarding expectations from in vitro studies because they all show apparent dose-independent kinetics in absorption or bioavailability and completeness of oral absorption is shown for most of the drugs evaluated. Conclusions: In spite of being substrates of intestinal efflux transporters such as P-gp, the in vivo oral absorption of 13 drugs examined apparently is not significantly impeded by efflux transporters. Thus, there may exist an apparent discrepancy between in vitro “expectations” and in vivo results; potential reasons for this are discussed. The present findings, however, do not de-emphasize potential in vivo importance of efflux transporters in affecting (increasing or decreasing) oral absorption of certain substrate drugs, especially those with low to moderate intestinal permeability and with low therapeutic index, or the importance of efflux transporters in the study of mechanisms of drug absorption and some potentially clinically significant drug-drug and drug-food interactions.Correspondence to:
Prof. Dr. W.L. Chiou; Department of Pharmaceutics and Pharmacodynamics (M/C 865), University of Illinois at Chicago, 833 South Wood, Chicago, IL 60612, USA
Interactions
Emedastine-ketoconazole: pharmacokinetic and pharmacodynamic interactions in healthy volunteers
U. Herranz, A. Rusca and A. Assandri
Abstract
U. Herranz, A. Rusca and A. Assandri
Cross Research S.A., Arzo, TI, Switzerland
Objective: To assess the pharmacokinetic and pharmacodynamic interactions of emedastine difumarate, a new antihistamine drug and ketoconazole. Material: Twelve healthy Caucasian volunteers were administered emedastine difumarate 4 mg oral capsules once daily for 10 consecutive days. From day 6 to day 10, ketoconazole 200 mg were co-administered twice daily. Methods: The effects of multiple ketoconazole administration on emedastine kinetics were evaluated by comparing values obtained for pharmacokinetic parameters at steady state, with and without ketoconazole. Css,max, Css,min, tmax, AUCss, t1/2 and Clss/F values, obtained after both treatments, were compared. Significant difference was defined as p < 0.05. QTc intervals from ECGs at baseline, after emedastine treatment and after emedastine-ketoconazole co-treatment were statistically compared. Results: Emedastine steady state pharmacokinetics were slightly altered as a result of the ketoconazole co-treatment. AUCss rose by about 33% (increase ranging from 0.96 to 66.86, p < 0.001) and total clearance decreased by about 30% (ranging from 0.96 to 40.08, p < 0.001) with no change in the half-life. These events did not lead to relevant pharmacodynamic changes, i.e. maximum prolongation of the corrected QT interval (QTc) observed after 5 days co-treatment (day 10) was of about 4%. Rate and severity of anti-H1 sedation episodes also did not increase on ketoconazole co-treatment. Conclusions: A moderate, but statistically significant interaction between emedastine and ketoconazole was observed. Pharmacodynamic data indicate no increase in the QTc interval during concomitant therapy. This result is consistent with the multiple emedastine metabolic pathways shown in man which supplement the metabolism by different enzymatic isoforms of CYP450. Concomitant treatment with emedastine and ketoconazole in subjects with normal QT intervals can therefore, be undertaken without special precautions.Correspondence to:
Dr. U. Herranz; Cross Research S.A., Via Giorgioli, CH-6864 Arzo, TI, Switzerland
Email: crossresearch@bluewin.ch
Pharmacodynamics/Pharmacoeconomics
A randomized trial to compare the efficacy, safety, cost and platelet aggregation effects of enoxaparin and unfractionated heparin (the ESCAPEU trial)
S. Malhotra, V.K. Bhargava, A. Grover, P. Pandhi and Y.P. Sharma
Abstract
S. Malhotra1, V.K. Bhargava1, A. Grover2, P. Pandhi1 and Y.P. Sharma2
1Department of Pharmacology, and 2Department of Cardiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Objective: To compare the efficacy, safety, cost and effects on platelet aggregation of unfractionated heparin and low-molecular weight heparin in unstable angina patients. Patients and methods: Ninety-three patients with unstable angina were randomized to receive either unfractionated heparin (UFH) or enoxaparin in an open design clinical trial with blinded end point evaluation. The effects of the heparins on platelet aggregation were also compared. Results: The composite end point of myocardial infarction, cardiac death, recurrent angina and need for intervention was observed in 62% of patients treated with UFH and in 37% of patients treated with enoxaparin (RR 1.7, 95% CI 0.75 to 3.71, p = 0.04). There was no difference in the frequency or severity of adverse events. A cost-effectiveness analysis showed both the heparins to be similar. Platelet aggregation was inhibited to a greater extent by UFH when compared to enoxaparin. Conclusions: Enoxaparin appears to be superior in efficacy to UFH and similar to UFH in safety. No difference in costs was detected in this study. The greater inhibition of platelet aggregation observed in the case of UFH compared to enoxaparin indicates that there may be more bleeding complications with UFH.Correspondence to:
Prof. Dr. V.K. Bhargava; Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Email: medinst@pgi.chd.nic.in
Therapy
A comparative study of caudal bupivacaine and midazolam-bupivacaine mixture for post-operative analgesia in children undergoing genitourinary surgery
R. Mahajan, Y.K. Batra, V.K. Grover and J. Kajal
Abstract
R. Mahajan, Y.K. Batra, V.K. Grover and J. Kajal
Department of Anesthesiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Objective: This study was designed to evaluate the analgesic efficacy of caudal midazolam-bupivacaine combination in providing post-operative pain relief in children undergoing genitourinary surgery and to study the occurrence of adverse effects. Subjects and methods: Thirty children, aged 2 to 8 years, scheduled for genitourinary surgery were allocated randomly to receive either 0.25% bupivacaine 0.5 ml/kg (group B; n = 15) or 0.25% bupivacaine 0.5 ml/kg with 50 mg/kg midazolam (group BM; n = 15) by the caudal route immediately after induction of general anesthesia. Heart rate, arterial blood pressure and oxygen saturation were monitored throughout the study period. Post-operative pain was assessed at regular intervals for 12 hours using an objective pain score. Analgesia was supplemented whenever the pain score was ³ 4. Duration of analgesia, as well as the requirement of additional analgesics, were noted. Results: Lowest pain scores were observed with the addition of midazolam to caudal bupivacaine (p < 0.01). Duration of analgesia was longer in group BM (11 ± 0.5 h) as compared to group B (7.4 ± 2.1 hours) (p < 0.05). Fewer children (26.6%) required additional analgesia in the combination group whereas in group B, 60% of the children received analgesic supplements within 6 hours after surgery (p < 0.05). There were no significant changes in heart rate, blood pressure and oxygen saturation in both groups. We observed no untoward event in either of the groups. Conclusion: Caudal administration of bupivacaine-midazolam mixture prolongs post-operative analgesia compared to bupivacaine alone without causing any adverse effects.Correspondence to:
Dr. Y.K. Batra; Department of Anesthesiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Oncology
Protective effects of fosfomycin on cisplatin- induced nephrotoxicity in patients with lung cancer
N. Rojanasthien, B. Kumsorn, B. Atikachai, S. Leotrakul and S. Thongprasert
Abstract
N. Rojanasthien1, B. Kumsorn1, B. Atikachai2, S. Leotrakul2 and S. Thongprasert2
1Department of Pharmacology, and 2Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Subjects, material and methods: Protective effects of fosfomycin on cisplatin-induced nephrotoxicity have been previously reported, however, the proper time, duration and dosage of its administration were uncertain. Therefore, we investigated the protective effect of concurrent administration of twice-daily doses of 2 g fosfomycin for 5 days in 13 cisplatin-naïve lung cancer patients who were due to receive a single dose per cycle of 100 mg/m2 cisplatin. On each chemotherapeutic cycle, patients were randomly given cisplatin alone or cisplatin plus fosfomycin every 4 weeks for a maximum of 4 consecutive cycles. Indicators of nephrotoxicity, urinary N-acetyl-b-D-glucosaminidase (NAG) activity, serum creatinine (Scr) and creatinine clearance (Clcr) were determined the day before and at day 3 and day 6 after cisplatin administration. Results were compared and statistically analyzed by the non-parametric Mann-Whitney’s test. We found that the NAG activities obtained on day 0, day 3 and day 6 of the fosfomycin cycles were comparable to values obtained during the control cycles (p > 0.05). Moreover, the NAG activities on day 3 of both treatment cycles were significantly elevated from baseline (p < 0.01) and had normalized on day 6. There were no significant changes in serum creatinine and creatinine clearance. Conclusion: High-dose cisplatin induced reversible elevation of urinary NAG and concurrent administration of low-dose fosfomycin for 5 days had no effect on the enzymuria. In the prevention of cisplatin nephrotoxicity, a further study using dose escalation (8 to 12 g/d) of fosfomycin administered 2 to 3 days prior to cisplatin are required to demonstrate its nephroprotective effects.Correspondence to:
Dr. N. Rojanasthien; Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand 50200
Email: nrojanas@ med.cmu.ac.th
Pharmacokinetics
Effect of age and gender on the pharmacokinetics of ebastine after single and repeated dosing in healthy subjects
S. Rohatagi, M. Gillen, M. Aubeneau, C. Jan, B. Pandit, B.K. Jensen and G. Rhodes
Abstract
S. Rohatagi1, M. Gillen2, M. Aubeneau3, C. Jan3, B. Pandit1, B.K. Jensen4 and G. Rhodes1
1Department of Drug Metabolism and Pharmacokinetics, 2Department of Clinical Pharmacology, Aventis Pharmaceutical (Formerly Rhône Poulenc-Rorer), Collegeville, PA, USA, 3Department of Clinical Pharmacology, Aventis Pharmaceutical (Formerly Rhône Poulenc-Rorer), Antony, France and 4Aventis Pharmaceuticals, Drug Metabolism and Pharmacokinetics, Bridgewater, USA
Objectives: Ebastine is a potent and selective H1-receptor antagonist indicated for allergic rhinitis which undergoes extensive first pass metabolism by CYP3A4 to form an active metabolite, carebastine. The purpose of the study was to determine age- and gender-related differences in the pharmacokinetics of ebastine and carebastine. Methods: The upper recommended oral dose of 20 mg once daily was administered to 12 healthy young (22 to 38 years) and 12 healthy elderly (50 to 92 years; 8 m and 4 f) subjects for 5 days. Plasma concentrations of ebastine and carebastine were determined for 24 hours following the initial dose on Day 1 and for 72 hours following the dose on Day 5 using a sensitive LC/MS/MS assay. The minimum quantifiable limit (MQL) for the assay was 0.05 ng/ml and 1.0 ng/ml for ebastine and carebastine, respectively. Results: Mean area under the curve and Cmax values on Day 1 and Day 5 were similar for ebastine but approximately doubled for carebastine due to its longer half-life. Mean carebastine concentrations were approximately10 to 20 fold higher than mean ebastine concentrations. For young subjects, the mean (%CV) ebastine t1/2 was 5.76 (28.47) h and 20.38 (46.19) h on Day 1 and Day 5, respectively. Similarily, for young subjects, the mean (%CV) for carebastine t1/2 was 7.03 (23.21) h and 26.12 (23.39) h on Day 1 and Day 5, respectively. This apparent prolongation of t1/2 was probably due to lack of proper estimation of terminal half-life on Day 1 as fewer samples were collected for a shorter duration on Day 1. Using a multicomparison test for Cmin values, it was determined that steady state conditions were achieved by Day 5 for both age groups for ebastine and in young subjects for carebastine. The variability in ebastine pharmacokinetic parameters was higher than carebastine. A 50% increase in ebastine AUC0-24 and Cmax values in elderly subjects, with no changes in t1/2, could be explained by either increased absorption of ebastine in elderly subjects or due to a decrease in first pass metabolism. As ebastine shows a high first-pass effect, even a small change in this first pass can cause large changes in plasma exposure. The ebastine pharmacokinetic parameters for elderly subjects in this study lie between the values reported in young subjects in earlier studies. Hence, the apparent age-related pharmacokinetic difference for ebastine is probably due to the inherent variability in ebastine pharmacokinetics. There were no gender-related differences in either young or elderly subjects for mean AUC, Cmax, tmax and t1/2 ebastine and carebastine values. Ebastine was absorbed rapidly with a median tmax of 1.25 to 2.25 h for both healthy young and elderly males and females on Day 1 and Day 5. There was a delayed appearance of carebastine as expressed by median tmax of 4.0 to 5.0 h, which did not change with age, gender or repeated administration. There were no clinically relevant differences between the groups of subjects with respect to adverse events or safety parameters. Conclusions: Thus, ebastine can be safely administered to elderly subjects with no clinically important age- or gender related differences in the pharmacokinetics of ebastine/carebastine.Correspondence to:
Dr. S. Rohatagi; Drug Metabolism and Pharmacokinetics, Building M, Room 250, Aventis Pharmaceuticals, Route 202-206, PO Box 6800, Bridgewater, NJ-08807-0800, USA
