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TDF is converted to tenofovir (TFV) in circulation, which is subsequently cleared via tubular secretion by organic ion transporters (OATs; OAT1 and OAT3). Using <jats:italic>in vitro<\/jats:italic> kinetic parameters for TFV and the OAT1 and OAT3 inhibitor probenecid, a bottom\u2010up physiologically\u2010based pharmacokinetic model was successfully developed for the first time that accurately describes the probenecid\u2013TFV interaction. This model predicted an increase in TFV plasma exposure by 60%, which was within 15% of the observed clinical pharmacokinetic data, and a threefold decrease in renal cells exposure following coadministration of a 600\u00a0mg TDF dose with 2\u00a0g probenecid. 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