title: Few Drugs Display Flip-Flop Pharmacokinetics and These Are Primarily Associated with Classes 3 and 4 of the BDDCS.
abstract: This study was conducted to determine the number of drugs exhibiting flip-flop pharmacokinetics following oral (p.o.) dosing from immediate-release dosage forms and if they exhibit a common characteristic that may be predicted based on BDDCS classification. The literature was searched for drugs displaying flip-flop kinetics (i.e., absorption half-life larger than elimination half-life) in mammals in PubMed, via internet search engines and reviewing drug pharmacokinetic data. Twenty two drugs were identified as displaying flip-flop kinetics in humans (13 drugs), rat (nine drugs), monkey (three drugs), horse (two drugs), and/or rabbit (two drugs). Nineteen of the 22 drugs exhibiting flip-flop kinetics were BDDCS Classes 3 and 4. One of the three exceptions, meclofenamic acid (Class 2), was identified in the horse; however, it would not exhibit flip-flop kinetics in humans where the p.o. dosing terminal half-life is 1.4 h. The second, carvedilol, can be explained based on solubility issues, but the third sapropterin dihydrochloride (nominally Class 1) requires further consideration. The few drugs displaying p.o. flip-flop kinetics in humans are predominantly BDDCS Classes 3 and 4. New molecular entities predicted to be BDDCS Classes 3 and 4 could be liable to exhibit flip-flop kinetics when the elimination half life is short and should be suspected to be substrates for intestinal transporters.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California.
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Garrison
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California.|Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.
authors.forename: Selma
authors.initials: S
authors.lastname: Sahin
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California.
authors.forename: Leslie Z
authors.initials: LZ
authors.lastname: Benet
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001702:Biopharmaceutics / Q000145:classification*; D006207:Half-Life; D000882:Haplorhini; D006736:Horses; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007700:Kinetics; D026901:Membrane Transport Proteins / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000145:classification* / Q000378:metabolism*; D010599:Pharmacokinetics; D011817:Rabbits; D051381:Rats
chemical_list: D026901:Membrane Transport Proteins; D004364:Pharmaceutical Preparations
keywords: BDDCS; absorption; disposition; flip-flop pharmacokinetics; half-life; intestinal absorption; oral drug absorption; pharmacokinetics; transporters