Pharmacokinetics and activity of pamidronate (APD)
Başlık:
Pharmacokinetics and activity of pamidronate (APD)
Yazar:
Pongchaidecha, Manat, author.
ISBN:
9780438083899
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (278 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 76-08C.
Özet:
Pamidronate (aminohydroxypropylidene bisphosphonate disodium, APD), a stable analogue of pyrophosphate, is a potent geminal bisphosphonate effective in treatment of several conditions characterised by pathological increased bone resorption. Little is known about the disposition and pharmacokinetics of pamidronate in animals and humans, particularly following intravenous administration at different rates and durations of infusion. Furthermore, the site of action of pamidronate, proposed to reside solely in bone, has been questioned. The primary aims of this work were to investigate i) whether intravenous infusion of pamidronate of different duration influences the pharmacokinetics, tissue disposition, and body retention in animals and ii) whether bone is the sole site of action of pamidronate in vivo. Two different durations of infusion (4 hr vs 24 hr) of pamidronate at a clinically relevant dose (1 mg/kg) were investigated in the rat. Based on analysis of data from plasma, tissues and urine, the duration of infusion did not influence pharmacokinetic parameters such as initial half-life, total clearance, renal clearance, and non-renal clearance, or protein binding, tissue distribution and body retention of pamidronate. Increased bone resorption (measured by increased plasma calcium) induced by retinoid (ie arotinoid, Ro 13-6298) in thyroparathyroidectomized rats was used as an animal model for investigations into the site of action of pamidronate. The first study investigated the effect of administration time on inhibition of increased plasma calcium and on distribution of pamidronate into bone by giving the compound simultaneously with or seven days before administration of retinoid. The results indicate that pamidronate given seven days before administration of retinoid showed higher distribution into bone (ie tibia) and maintained the inhibitory effect on bone resorption. The second study was based on the working hypothesis that pamidronate distributing in certain organs (eg spleen, liver and lung) leading to inactivation of cells associated with osteoclast progenitors (eg monocytes and macrophages) might bring about the inhibition of osteoclastic bone resorption. Preliminary observations from this study suggest that although bone is the major site of action of the compound, pamidronate in spleen may be involved in the inhibition of bone resorption in this animal model. The secondary aim of this work was to investigate the general pharmacokinetics of pamidronate in humans, especially in patients with osteolytic bone disorders (ie bone metastases). First, the influence of duration of infusion (1 hr, 4 hr, 8 hr, and 24 hr) of pamidronate at a dose of 60 mg was examined in patients with bone metastases. The results supported the previous findings observed in rats that duration of infusion has no influence on pharmacokinetics and body retention of this compound. Additionally, the intersubject variability in protein binding (in vitro) of pamidronate was also investigated in normal volunteers (% bound ranging from 19-37 %). Second, the oral bioavailability of pamidronate was estimated in patients with bone metastases. The study was the first to assess oral absorption of pamidronate given as enteric-coated formulations, using chemical analysis of pamidronate in plasma and urine. Data obtained from a preliminary open parallel design study of pamidronate of two formulations (enteric-coated tablets and pellets) indicated that the oral absorption of pamidronate is poor (≈ 0.26 %) with high inter- and intra-patient variability. This work will help in the design of therapeutic regimens for administration of pamidronate in patients.
Notlar:
School code: 1543
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(686891.1) | 686891-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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