title: Pharmacokinetics and Bioavailability of the GnRH Analogs in the Form of Solution and Zn2+-Suspension After Single Subcutaneous Injection in Female Rats.
abstract: OBJECTIVE
  Although many synthetic gonadoliberin analogs have been developed, only a few of them, including buserelin, were introduced into clinical practice. Dalarelin, which differs from buserelin by just one aminoacid in the position 6 (D-Ala), is not widely used so far. Gonadotropin-releasing hormone (GnRH) analogs are used to treat many different illnesses and are available in different forms like solution for injection, nasal spray, microspheres, etc. Unfortunately, none of the above drug formulations can release the hormones for 24 h. We assumed that classical suspension could solve this problem.
  
  
  METHODS
  Two sets of experiments were performed. In the first one, buserelin and dalarelin were injected into mature female rats in two forms: suspension, in which the analogs are bounded by Zn2+ions and solution. The pharmacokinetic parameters and bioavailability of the analogs were calculated, based on their concentration in the plasma measured by high-performance liquid chromatography method (HPLC). In the second experiment, the hormones in two different forms were injected into superovulated immature female rats and then the concentration of Luteinizing hormone (LH), Follicle-stimulating hormone (FSH) and 17β-estradiol in the serum was measured by radioimmunological method.
  
  
  RESULTS
  The Extent of Biological Availability (EBA), calculated on the base of AUC0-∞, showed that in the form of solution buserelin and dalarelin display, respectively, only 13 and 8 % of biological availability of their suspension counterparts. Comparing both analogs, the EBA of dalarelin was half (53 %) that of buserelin delivered in the form of solution and 83 % when they were delivered in the form of suspension. The injection of buserelin or dalarelin, in the form of solution or suspension, into superovulated female rats increased LH, FSH and estradiol concentration in the serum. However, after injection of the analogs in the form of suspension, the high concentration of LH and FSH in the serum persisted longer.
  
  
  CONCLUSIONS
  Performed studies indicate that GnRH analogs in the form of suspension have higher bioavailability than their solution counterparts. It influences the effects of their action, especially in relation to LH and FSH.
authors.affiliation: Department of Histology, Medical University of Silesia, Medyków 18, 40-752, Katowice, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Suszka-Świtek
authors.affiliation: "Biochefa" Pharmaceutical Research Production Plant, Sosnowiec, Poland.
authors.forename: Florian
authors.initials: F
authors.lastname: Ryszka
authors.affiliation: Department of Applied Pharmacy, Medical University of Silesia, Sosnowiec, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Dolińska
authors.affiliation: Department of Radiology and Nuclear Medicine, Medical University of Silesia, Katowice, Poland.
authors.forename: Renata
authors.initials: R
authors.lastname: Dec
authors.affiliation: Department of Biochemistry, Medical University of Silesia, Katowice, Poland.
authors.forename: Alojzy
authors.initials: A
authors.lastname: Danch
authors.affiliation: Department of Histology, Medical University of Silesia, Medyków 18, 40-752, Katowice, Poland.
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Filipczyk
authors.affiliation: Department of Histology, Medical University of Silesia, Medyków 18, 40-752, Katowice, Poland. wiader@sum.edu.pl.
authors.forename: Ryszard
authors.initials: R
authors.lastname: Wiaderkiewicz
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002064:Buserelin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004958:Estradiol / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D007279:Injections, Subcutaneous; D007986:Luteinizing Hormone / Q000097:blood; D019999:Pharmaceutical Solutions; D051381:Rats; D017208:Rats, Wistar; D013535:Suspensions; D013997:Time Factors; D015032:Zinc / Q000737:chemistry*
chemical_list: D019999:Pharmaceutical Solutions; D013535:Suspensions; C404725:dalarelin; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D015032:Zinc; D002064:Buserelin