How Transporters Have Changed Basic Pharmacokinetic Understanding
The emergence and continued evolution of the transporter field has caused re-evaluation and refinement of the original principles surrounding drug disposition. In this paper, we emphasize the impact that transporters can have on volume of distribution and how this can affect the other major pharmacokinetic parameters. When metabolic drug–drug interactions or pharmacogenomic variance changes the metabolism of a drug, the volume of distribution appears to be unchanged while clearance, bioavailability, and half-life are changed. When transporters are involved in the drug–drug interactions or pharmacogenomic variance, the volume of distribution can be markedly affected causing counterintuitive changes in half-life. Cases are examined where a volume of distribution change is significant enough that although clearance decreases, half-life decreases. Thus, drug dosing decisions must be made based on CL/F changes, not half-life changes, as such volume of distribution alterations will also influence the half-life results.
Key Wordsclearance half-life mean residence time transporters volume of distribution
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflicts of interest to disclose.
- 1.Benet LZ. Pharmacokinetics: basic principles and its use as a tool in drug metabolism. In: Mitchell JR, Horning MG, editors. Drug metabolism and drug toxicity. New York: Raven Press; 1984. p. 199–211.Google Scholar
- 2.Benet LZ, Sheiner LB. Introduction: pharmacokinetics: the dynamics of drug absorption, distribution, and elimination. In: Gilman AG, Goodman LS, Rall TW, Murad F, editors. The pharmacological basis of therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985. Chapter 1. p. 1–34.Google Scholar
- 3.Benet LZ. Introductory lecture, “Pharmacokinetics for pharmaceutical scientists”, UCSF one week course first taught February 1986 and continuously each year since.Google Scholar
- 11.Zheng HX, Huang Y, Frassetto LA, Benet LZ. Elucidating rifampin’s inducing and inhibiting effects on glyburide pharmacokinetics and blood glucose in healthy volunteers: unmasking the differential effects of enzyme induction and transporter inhibition for a drug and its primary metabolite. Clin Pharmacol Ther. 2009;85:78–85.CrossRefPubMedGoogle Scholar