title: Approaches to intravenous clinical pharmacokinetics: Recent developments with isotopic microtracers.
abstract: Obtaining pharmacokinetic data from the intravenous route for drugs intended for oral administration has traditionally been expensive and time consuming because of the toxicology requirements and challenges in intravenous formulations. Such studies are necessary, however, particularly when regulator agencies request absolute bioavailability data. A method has emerged whereby the drug administered intravenously is isotopically labeled and dosed at a maximum of 100 µg concomitantly with an oral administration given at a therapeutically relevant level. The intravenous administration has been termed a microtracer and obviates intravenous toxicology requirements as well as simplifying formulations. The study design also essentially removes issues of nonlinear pharmacokinetics that may occur when oral and intravenous doses are administered separately. This review examines the methodology and the literature to date, including those studies intended for regulatory submission. The method has been extended to the study of prodrug-to-active drug kinetics and to obtaining clearance, volume of distribution, and absolute bioavailability at steady-state conditions.
authors.affiliation: Visiting Professor of Pharmacology, School of Pharmacy, University of Lincoln, Lincoln, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Lappin
mesh_terms: D061605:Administration, Intravenous; D000596:Amino Acids / Q000493:pharmacokinetics; D000813:Anilides / Q000493:pharmacokinetics; D000818:Animals; D001559:Benzhydryl Compounds / Q000493:pharmacokinetics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics; D003499:Cyclic S-Oxides / Q000493:pharmacokinetics; D005960:Glucosides / Q000493:pharmacokinetics; D064368:Healthy Volunteers; D006801:Humans; D007553:Isotope Labeling; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000378:metabolism; D010599:Pharmacokinetics; D011725:Pyridines / Q000493:pharmacokinetics; D012855:Sitosterols / Q000493:pharmacokinetics
chemical_list: C517803:4-aminho-2-thiabicyclo(3.1.0)hexane-4,6-dicarboxylic acid; D000596:Amino Acids; D000813:Anilides; D001559:Benzhydryl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003499:Cyclic S-Oxides; D005960:Glucosides; C538724:HhAntag691; C534551:LY 2140023; D004364:Pharmaceutical Preparations; D011725:Pyridines; D012855:Sitosterols; C025473:gamma-sitosterol; C575086:6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-1(3H),2'-(2H)pyran)-3',4',5'-triol
keywords: absolute bioavailability; accelerator mass spectrometry; clearance; intravenous administration; isotopic tracer; microtracer; steady state; volume of distribution