title: Simultaneous magnetic resonance imaging and pharmacokinetic analysis of intramuscular depots.
abstract: The present pilot study introduces a method that might give novel insights in drug absorption processes from intramuscularly administered depots. An oily suspension or an aqueous solution of paracetamol (6 mg/kg body mass), prednisolone or its hemisuccinate sodium salt for the aqueous solutions (10mg/kg body mass) or diclofenac (10mg/kg body mass) was injected into the muscle tissue of the hind leg of female Lewis-rats (n=47). For the oily suspensions the micronized particles were suspended in medium-chain triglycerides. The aqueous solutions were buffered to a pH of 7.4 ± 0.5. Polyethylene glycol was added as a cosolvent in the formulations containing paracetamol (acetaminophen) and diclofenac and sodium chloride was added to the aqueous solutions of prednisolone hemisuccinate sodium to achieve nearly isotonic formulations. The formed depot was visualized by magnetic resonance imaging (MRI) and characterized with regard to volume and surface area. A 7 T-small animal scanner was used and T1-weighted and T2-weighted sequences including a fat saturation were performed. Simultaneously blood samples were taken and the drugs were quantitatively analyzed. The water based solvent and the oily dispersion agent were visible in the MRI images without the use of contrast agents. Since a free hand injection mostly led to an application directly into the fascia, resulting in a fast removal of the depot, MRI-guided injection was conducted. Comparing pharmacokinetic data with MRI data it was observed that maximal blood levels occurred before the solvent and the dispersion agent were removed from the muscle tissue. Thus, the drug is not absorbed together with the depot. Furthermore, no correlation was found between the shape of the depot and the rate of absorption. Consequently, a higher surface area or volume of the depot did not result in a faster release or absorption of the drugs from the tested formulations. In contrast to the paracetamol and prednisolone formulations the formulations containing diclofenac led to a massive accumulation of interstitial fluid around the injection area being a sign for an acute local reaction. Histological analysis of the muscle tissue revealed a clear correspondence between the amount of interstitial fluid and the extent of infiltrating lymphocytes and granulocytes indicating a tissue response. In conclusion combining MRI with pharmacokinetic data is a suitable method to gain deeper insights into drug absorption processes from intramuscular depots. Furthermore, MRI offers a great possibility detecting local side effects caused by an intramuscularly applied dosage form. This might be very useful in preclinical phases during the development of new intramuscular formulations.
authors.affiliation: Institute of Pharmacy, Department of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption and Transport (C_DAT), Ernst Moritz Arndt University Greifswald, Felix-Hausdorff-Straße 3, D-17487 Greifswald, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Probst
authors.affiliation: Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, D-17475 Greifswald, Germany.
authors.forename: Jens-Peter
authors.initials: JP
authors.lastname: Kühn
authors.affiliation: Institute of Pharmacology, Department of Clinical Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Felix-Hausdorff-Straße 3, D-17487 Greifswald, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Scheuch
authors.affiliation: Institute of Pharmacy, Department of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption and Transport (C_DAT), Ernst Moritz Arndt University Greifswald, Felix-Hausdorff-Straße 3, D-17487 Greifswald, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Seidlitz
authors.affiliation: Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, D-17475 Greifswald, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hadlich
authors.affiliation: Institute of Pathology, University Medicine Greifswald, Friedrich-Loeffler-Straße 23e, D-17489 Greifswald, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Evert
authors.affiliation: Institute of Pharmacology, Department of Clinical Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Felix-Hausdorff-Straße 3, D-17487 Greifswald, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Oswald
authors.affiliation: Institute of Pharmacology, Department of Clinical Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Felix-Hausdorff-Straße 3, D-17487 Greifswald, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Siegmund
authors.affiliation: Institute of Pharmacy, Department of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption and Transport (C_DAT), Ernst Moritz Arndt University Greifswald, Felix-Hausdorff-Straße 3, D-17487 Greifswald, Germany. Electronic address: werner.weitschies@uni-greifswald.de.
authors.forename: Werner
authors.initials: W
authors.lastname: Weitschies
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004008:Diclofenac / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D007273:Injections, Intramuscular; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009132:Muscles / Q000378:metabolism; D009821:Oils / Q000032:analysis; D014677:Pharmaceutical Vehicles / Q000032:analysis; D011239:Prednisolone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011917:Rats, Inbred Lew
chemical_list: D018712:Analgesics, Non-Narcotic; D000893:Anti-Inflammatory Agents; D009821:Oils; D014677:Pharmaceutical Vehicles; D004008:Diclofenac; D000082:Acetaminophen; D011239:Prednisolone
keywords: Aqueous solution; Depot volume and surface area; Intramuscular; Magnetic resonance imaging; Oily suspension