title: Effects of controlled-release on the pharmacokinetics and absorption characteristics of a compound undergoing intestinal efflux in humans.
abstract: OBJECTIVE
  The number of active pharmaceutical ingredients (API) undergoing inhibitable and saturable intestinal efflux is considerable. As a consequence, absorption and bioavailability may depend on the intestinal concentration profile of the drug and may vary as a function of dose and release rate of the drug from the dosage form. The impact of controlled versus immediate-release on the absorption of P-glycoprotein substrates is currently unknown. Thus, the main focus of the present study was a comparison of the pharmacokinetics of the P-gp model substrate talinolol following administration of immediate-release (IR) and controlled-release (CR) tablets to healthy human volunteers with a particular focus on the absorption characteristics of the active pharmaceutical ingredients.
  
  
  METHODS
  Talinolol immediate-release (Cordanum), 100mg), one controlled-release (100mg) and two controlled-release tablets (200mg) were administered as single doses to fasting healthy volunteers in a crossover design with a 1 week washout period between treatments. Sufficient blood and urine samples were drawn and analysed using a specific HPLC method with UV detection to describe the resulting plasma and urinary excretion versus time profiles.
  
  
  RESULTS
  The bioavailability of talinolol in term of AUC(0-->infinity) for IR talinolol was approximately twice as high as compared to the administration of the same dose in a controlled-release dosage form. After administration of talinolol IR tablets, the drug was rapidly absorbed and reached maximum concentrations C(max) of 204.5 ng/ml+/-121.8 (means+/-S.D.) 2h after dosing. The terminal half-life of the drug averaged 19.8h following IR administration in comparison to 32 h under CR dosing conditions. Following administration of the IR dosage form, significant secondary peaks were observed in one healthy subject. Secondary peaks were not clearly apparent in the CR plasma profiles.
  
  
  CONCLUSIONS
  The present study demonstrates a considerable loss of bioavailability of drugs that are substrates of intestinal secretory transporters upon their administration in controlled-release dosage forms.
authors.affiliation: Biopharmacy und Pharmaceutical Technology, Institute for Pharmacy, Johannes Gutenberg-University, Staudinger Weg 5, 55099 Mainz, Germany.
authors.forename: Marija
authors.initials: M
authors.lastname: Tubic
authors.forename: Daniel
authors.initials: D
authors.lastname: Wagner
authors.forename: Hildegard
authors.initials: H
authors.lastname: Spahn-Langguth
authors.forename: Christine
authors.initials: C
authors.lastname: Weiler
authors.forename: Roland
authors.initials: R
authors.lastname: Wanitschke
authors.forename: Wulf Otto
authors.initials: WO
authors.lastname: Böcher
authors.forename: Peter
authors.initials: P
authors.lastname: Langguth
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000328:Adult; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D011412:Propanolamines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D012995:Solubility; D013607:Tablets
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003692:Delayed-Action Preparations; D011412:Propanolamines; D013607:Tablets; C011550:talinolol