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Pharmacokinetics and Bioavailability of the Gnrh Analogs in the Form of Solution and Zn2+-Suspension After Single Subcutaneous Injection in Female Rats

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Pharmacokinetics and Bioavailability of the Gnrh Analogs in the Form of Solution and Zn2+-Suspension After Single Subcutaneous Injection in Female Rats Eur J Drug Metab Pharmacokinet (2017) 42:251–259 DOI 10.1007/s13318-016-0342-5 ORIGINAL RESEARCH ARTICLE Pharmacokinetics and Bioavailability of the GnRH Analogs in the Form of Solution and Zn2+-Suspension After Single Subcutaneous Injection in Female Rats 1 2 3 Aleksandra Suszka-S´witek • Florian Ryszka • Barbara Dolin´ska • 4 5 1 1 Renata Dec • Alojzy Danch • Łukasz Filipczyk • Ryszard Wiaderkiewicz Published online: 14 May 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Follicle-stimulating hormone (FSH) and 17b-estradiol in the Background and Objectives Although many synthetic serum was measured by radioimmunological method. gonadoliberin analogs have been developed, only a few of Results The Extent of Biological Availability (EBA), calcu- them, including buserelin, were introduced into clinical lated on the base of AUC0-?, showed that in the form of practice. Dalarelin, which differs from buserelin by just solution buserelin and dalarelin display, respectively, only 13 one aminoacid in the position 6 (D-Ala), is not widely used and 8 % of biological availability of their suspension coun- so far. Gonadotropin-releasing hormone (GnRH) analogs terparts. Comparing both analogs, the EBA of dalarelin was are used to treat many different illnesses and are available half (53 %) that of buserelin delivered in the form of solution in different forms like solution for injection, nasal spray, and 83 % when they were delivered in the form of suspension. microspheres, etc. Unfortunately, none of the above drug The injection of buserelin or dalarelin, in the form of solution formulations can release the hormones for 24 h. We or suspension, into superovulated female rats increased LH, assumed that classical suspension could solve this problem. FSH and estradiol concentration in the serum. However, after Methods Two sets of experiments were performed. In the injection of the analogs in the form of suspension, the high first one, buserelin and dalarelin were injected into mature concentration of LH and FSH in the serum persisted longer. female rats in two forms: suspension, in which the analogs Conclusion Performed studies indicate that GnRH analogs are bounded by Zn2? ions and solution. The pharmacokinetic in the form of suspension have higher bioavailability than parameters and bioavailability of the analogs were calcu- their solution counterparts. It influences the effects of their lated, based on their concentration in the plasma measured by action, especially in relation to LH and FSH. high-performance liquid chromatography method (HPLC). In the second experiment, the hormones in two different forms were injected into superovulated immature female rats Key Points and then the concentration of Luteinizing hormone (LH), Pharmacokinetic parameters (absorption rate & Ryszard Wiaderkiewicz constant (ka) and elimination rate constant (ke)) of [email protected] gonadotropin releasing hormone (GnRH) analogs 1 differ depending on their formulation. The prolonged Department of Histology, Medical University of Silesia, absorption and elimination is observed if analogs are Medyko´w 18, 40-752 Katowice, Poland delivered in the form of suspension. 2 ‘‘Biochefa’’ Pharmaceutical Research Production Plant, Sosnowiec, Poland Extent of Biological Availability (EBA) of both 3 Department of Applied Pharmacy, Medical University of buserelin and dalarelin in the form of suspension is Silesia, Sosnowiec, Poland higher than in the form of solution. 4 Department of Radiology and Nuclear Medicine, Medical Higher bioavailability of GnRH analogs in the form University of Silesia, Katowice, Poland of suspension correlates with hormonal profiles of 5 Department of Biochemistry, Medical University of Silesia, LH and FSH in the serum. Katowice, Poland 252 A. Suszka-S´witek et al. 1 Introduction the hormone 2–3 times daily in the form of solution by injection or nasal spray. Kochman et al. [14] studied the influence of Cu2?,Ni2? and Zn2? ions forming the com- Since the discovery of gonadoliberin, many synthetic plexes with GnRH on the release of FSH and LH from analogs, both its agonists or antagonists, have been pituitary (in vivo model) and compared affinity of these developed. However, so far only a few of them were complexes to binding sites of GnRH receptors from ante- introduced into clinical practice. Active analogs in the rior pituitary of female rats (in vitro model). The studies agonists group are most often made by modifications in the in vivo show that complex of GnRH with Cu2? ions causes position 6 and 10. Usually, glycine in position 6 is replaced big surge of both FSH and LH from pituitary. Effectiveness with more lipophilic D-aminoacid like D-Phe, D-Leu or of complexes containing Zn2? ions was comparable to D-Trp and glycinamide in position 10 is substituted by natural GnRH and the less effective was complexes with ethylamide. These substitutions result in more hydrophobic Ni2? ions. Taking above into consideration, we decided to compounds having not only increased affinity to GnRH analyze the classical suspensions in which GnRH analogs receptors, but also prolonged half-life due to increased form complexes with Zn2? ions. resistance to proteolytic degradation. As such, synthetic The aim of our study was to analyze and compare the analogs are characterized by higher activity than endoge- basic pharmacokinetic parameters and bioavailability of nous GnRH [1–3]. burserelin and dalarelin delivered to female rats in 2 dif- One of the agonists used in clinical practice is burserelin ferent forms: solution for injection and suspension con- of m.w. 1239 D. Replacement of Gly in position 6 by taining hormone complexed with Zn2? ions. We have also D-Ser(tBu) and Gly-NH in position 10 by ethylamide 2 analyzed the biological effect of both forms by assessing N-EtNH increases its activity, in relation to natural GnRH, 2 the hormonal profiles of FSH, LH and 17b-estradiol in the by 20 times [4]. Dalarelin, in contrary to buserelin, is not so serum of superovulated immature female rats. broadly used. It also belongs to agonists group, have m.w. 1167 D and is different from burserelin by having in position 6 D-Ala. Its relative potency is roughly 14 times 2 Materials and Methods higher than natural gonadoliberin [4]. Studies performed by Colin and Jameson [5] on the cells from rats anterior 2.1 Animals pituitary proved that this peptide, like other GnRH analogs, binds to GnRH receptor and activates intracellular The animal experiments were performed at the Center for pathways. Experimental Medicine, Medical University of Silesia in GnRH analogs are commonly used in clinical practice. Katowice, Poland. The rats were housed at 22 °C with a They are used in the diagnosis of hypothalamus–pituitary– regular 12/12 light–darkness cycle with access to standard gonadal axis, to induce and normalize activities of pituitary Murigran chow and water ad libitum. All procedures per- gland, in vitro fertilization (IVF) programs and long-term formed in studies involving animals were in accordance inhibition of pituitary–gonadal axis [4, 6–8]. Such a with the ethical standards of the institution at which the diversity of applications leads to the development of few studies were conducted. Research was approved by the formulations of drugs containing GnRH analogs. They are Local Ethical Committee for Animal Experimentation at available as solution for injection, nasal spray, short release the Medical University of Silesia. [9] or prolonged release [10] forms like implants, micro- Experiment 1. To validate biological availability and to spheres [11], micro- and nanoparticles [9, 11, 12]. In case measure basic pharmacokinetic parameters, we used of long-term depot (even few months), GnRH analogs are female rats (Wistar strain) weighting 200–210 g. Animals embedded in biodegradable polymer like poly-D,L-lactide were divided into 4 groups (5 rats each) which received (PLA) and poly D,L-lactide-co glycolide (PLGA) [13]. subcutaneous injection (6 mg/kg) of buserelin acetate or Microspheres, micro- and nanoparticles are delivered dalarelin acetate in the form of solution (group I and group subcutaneously or intramuscularly in the form of suspen- III, respectively) or in the form of suspension (group II and sion and are characterized by slow release or controlled group IV, respectively). At 15 and 30 min, then 1, 2, 3, 4, release with zero-order kinetics. No formulation is avail- 5, 8, 12 and 24 h after analogs injection 250 ll of blood able which would release analogs for 24 h. In our opinion, was drawn from tail vein into heparinized pipettes. The such a formula could be a classical suspension where collected blood was kept on ice in the tubes containing analog is bound to inorganic ion, as in some insulin heparin and, to inactivate proteases, 500 KIU/ml of preparations. Such a drug formula could be very useful if Aprotinin (Traskolan, Jelfa S.A., Jelenia Go´ra, Poland). only a few days of treatment with analogs is required. The tubes were then centrifuged for 20 min at 0 °C and Presently, the only option in such a situation is to deliver 5000 rev/min. The obtained plasma was mixed with 10 % Pharmacokinetics and Bioavailability of the GnRH Analogs 253 trichloroacetic acid (1:1, v/v) and centrifuged again for 2.3 Measurement of GnRH Analogs Concentration 15 min at 15000 rev/min. The concentrations of buserelin by HPLC and dalarelin were measured by HPLC method. Experiment 2. To validate hormonal profile in the Concentration of studied analogs was measured by modi- serum, we used immature female rats (Wistar strain) fied HPLC method acc. to Kertscher et al. [16]. The weighting 40–45 g. Animals were divided into 4 experi- modifications were: change in flow speed (from 1 ml/min mental groups and 1 control group (40 rats each). Experi- to 0.8 ml/min) and change in excitation wave (from ment was performed according to Ovarian Ascorbic Acid 280 nm to 274 nm) and emission wave (from 365 nm to Depletation (OAAD) method [15].
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