title: Prediction of human renal clearance from preclinical species for a diverse set of drugs that exhibit both active secretion and net reabsorption.
abstract: Identifying any extrahepatic excretion phenomenon in preclinical species is crucial for an accurate prediction of the pharmacokinetics in man. This understanding is particularly key for drugs with a small volume of distribution, because they require an especially low total clearance to be suitable for a once-a-day dosing regimen in man. In this study, three animal scaling techniques were applied for the prediction of the human renal clearance of 36 diverse drugs that show active secretion or net reabsorption: 1) direct correlations between renal clearance in man and each of the two main preclinical species (rat and dog); 2) simple allometry; and 3) Mahmood's renal clearance scaling method. The results show clearly that the predictions to man for the methods are improved significantly when corrections are made for species differences in plasma protein binding. Overall, the most accurate predictions were obtained by using a direct correlation with the dog renal clearance after correcting for differences in plasma protein binding and kidney blood flow (r² = 0.84), where predictions, on average, were within 2-fold of the observed renal clearance values in human.
authors.affiliation: Department of Discovery DMPK, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE115RH, United Kingdom. stuart.paine@hotmail.co.uk
authors.forename: Stuart W
authors.initials: SW
authors.lastname: Paine
authors.forename: Karelle
authors.initials: K
authors.lastname: Ménochet
authors.forename: Rebecca
authors.initials: R
authors.lastname: Denton
authors.forename: Dermot F
authors.initials: DF
authors.lastname: McGinnity
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Riley
mesh_terms: D000042:Absorption; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000706:statistics & numerical data; D015507:Drugs, Investigational / Q000493:pharmacokinetics; D006801:Humans; D008658:Inactivation, Metabolic; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008432:Mathematical Computing; D008657:Metabolic Clearance Rate; D004364:Pharmaceutical Preparations / Q000097:blood*; D011237:Predictive Value of Tests; D011485:Protein Binding; D051381:Rats; D013045:Species Specificity
chemical_list: D001798:Blood Proteins; D015507:Drugs, Investigational; D004364:Pharmaceutical Preparations