Research ArticlesPrediction of Pharmacokinetics Prior to In Vivo Studies. 1. Mechanism‐Based Prediction of Volume of Distribution
Section snippets
INTRODUCTION
The volume of distribution at steady state (Vss) and clearance processes characterize the disposition of drugs. The estimation of Vss is therefore essential. Vss corresponds to the equivalent plasma volume in which a drug is distributed into the body. In fact, Vss would equal the plasma volume in addition to the sum of each tissue: plasma partition coefficient (Pt:p) multiplied with its respective tissue volume.1 The Pt:p represents the concentration ratio between a tissue and plasma at steady
METHODS
The overall method was based on a conventional equation that describes Vss. In this equation the input parameters relative to tissue distribution (i.e., Pt:p's) were predicted from established tissue composition‐based equations, whereas the input parameters relative to the species (tissue volumes) were obtained from the literature. Two kinds of drugs were considered: those for which a homogeneous distribution into a tissue by passive diffusion can be assumed, and those for which a distribution
RESULTS
It is of interest to note that fitting exercises were omitted to improve the predictions. In fact, the current study presents only first predictions of Vss by using one set of specified data as the input in eq. 1. The experimental values of Vssin vivo obtained from the literature for 123 drugs were compared with the corresponding predicted values. For the 123 drugs investigated in the present study the overall average ratio of predicted‐to‐mean experimental rat and human Vss values was 1.06
DISCUSSION
Distribution and clearances are input parameters in empirical PK compartment models and physiologically based PK models (PBPK).3,30 For efficient screening efforts with these models it is essential to obtain rough predictions of Vss and clearances from compound‐specific determinants routinely determined in early drug discovery. In the present study, a mechanism‐based method for predicting rat and human Vss under in vivo conditions has been developed and validated for 123 structurally unrelated
Acknowledgements
We thank Dr. Wolfgang F. Richter and Prof. Theodor W. Guentert, at F. Hoffmann‐La Roche Ltd., for the revision of the manuscript.
REFERENCES (208)
- et al.
A priori prediction of tissue:plasma partition coefficients of drugs to facilitate the use of physiologically based pharmacokinetic models in drug discovery
J Pharm Sci
(2000) - et al.
Prediction of adipose tissue:plasma partition coefficients for structurally unrelated drugs
J Pharm Sci
(2001) - et al.
Narcotic and narcotic antagonist pKa's and partition coefficients and their significance in clinical practice
Drug Alcohol Dependence
(1975/76) - et al.
Pharmacokinetic study on the mechanism of tissue distribution of doxorubicin: interorgan and interspecies variation of tissue‐to‐plasma coefficients in rats, rabbits, and guinea pigs
J Pharm Sci
(1984) - et al.
Sex differences in the biliary excretion of digoxin and its metabolism in aging Wistar rats
Arch Gerontol Geriatr
(1985) - et al.
Pharmacokinetics of acetaminophen after intravenous and oral administration to spontaneously hypertensive rats and normotensive Wistar rats
J Pharm Sci
(1994) - et al.
Comparative binding of etretinate and acitretin to plasma proteins and erythrocytes
Biochem Pharmacol
(1992) - et al.
Metronidazole phosphate a water soluble prodrug for parental solutions of metronidazole
J Pharm Sci
(1982) - et al.
Voltammetric and spectophotometric techniques for the determination of the antihypertensive drug prazosin in urine and formulations
J Pharm Biomed Anal
(1999) - et al.
Physicochemical properties, solubility, and protein binding of Δ9‐tetrahydrocannabinol
J Pharm Sci
(1974)
Assay and disposition of carvedilol enantiomers in humans and monkeys: evidence of stereoselective presystemic metabolism
J Pharm Sci
Characterization of the properties of cocaine in blood: blood clearance, blood to plasma ratio, and plasma protein binding
J Pharm Sci
Dose‐response cocaine pharmacokinetics and metabolite profile following intravenous administration and arterial sampling in unanesthetized, freely moving male rats
Neurotoxicol Teratol
Comparison of the pharmacokinetics of etomidate in children and in adults
Ann Fr Anesth Reanim
Pharmacokinetics of etomidate
Ann Fr Anesth Reanim
Pharmacokinetics of fentanyl in the elderly
Br J Anaesth
Prediction of the volume of distribution of basic drugs in human based on data from animals
J Pharmacokinet Biopharm
In vitro and in vivo evaluation of the tissue‐to‐blood partition coefficients for physiological pharmacokinetic models
J Pharmacokinet Biopharm
Pharmacokinetics
Prediction of the volume of distribution from in vitro data and use for estimating the absolute extent of absorption
Int J Clin Pharmacol Toxicol
Prediction of apparent volume of distribution in obesity
Meth Find Exp Clin Pharmacol
True oil/water partition coefficients of procaine and lidocaine and estimation of their dissociation constants in organic solvents
Anesthesia Analgesia
Partition coefficients and their uses
Chem Rev
The binding of thiopental to human serum albumin at variable pH and temperature
Acta Pharmacol Toxicol
The binding of drugs to blood plasma macromolecules: recent advances and therapeutic significance
Adv Drug Res
Analysis of nonlinear tissue distribution of quinidine in rats by physiologically based pharmacokinetics
J Pharmacokinet Biopharm
The anomalous pharmacokinetics of amiodarone explained by nonexponential tissue trapping
J Pharmacokinet Biopharm
Uptake of basis drugs into rat lung granule fraction in vitro
Biol Pharm Bull
Effects of basic drugs on the hepatic transport of cardiac glycosides in rats
Biochem Pharmacol
Biopharmaceutical studies on drug/conjugated‐metabolite interactions. III. Effect of acetaminophen sulfate and its positional isomers on the pharmacokinetics of acetaminophen in rats
Biol Pharm Bull
The binding of paracetamol to plasma proteins of man and pig
J Pharm Pharmac
Obesity, sex, and acetaminophen disposition
Clin Pharmacol Ther
Differential effects of fluorbiprofen and aspirin on acetazolamide disposition in humans
Br J Clin Pharmacol
Synthesis and physicochemical properties of thiadiazol as candidates for topically effective carbonic anhydrase inhibitors
J Med Chem
Systemic pharmacokinetics of acethylenic retinoids in rats
Drug Metab Dispos
Lipid solubility and drug penetration of the blood brain barrier
Proc Soc Exp Biol Med
Pharmacokinetics of ascorbic acid in man
Eur J Clin Pharmacol
Quantitative structure‐pharmacokinetics relationships: I. Development of a whole‐body physiologically based model to characterise changes in pharmacokinetics across a homologous series of barbiturates in the rat
J Pharmacokinet Biopharm
Pharmacokinetics of captopril in healthy subjects and in patients with cardiovascular diseases
Clin Pharmacokin
Physiologically based pharmacokinetic model of 2,3‐dideoxyinosine
Pharm Res
Mephenytoin stereoselective elimination in the rat. I. Enantiomeric disposition following intravenous administration
Eur J Metab Pharmacokin
Mephenytoin stereoselective elimination in the rat. II. Comparison of mephenytoin stereoselective clearance during chronic intravenous and hepatic portal vein administration
Eur J Metab Pharmacokin
Physicochemical considerations and pharmacokinetic behaviour in delivery of drugs to the central nervous system
Cancer Treat Rep
Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials
Clin Pharmacokinet
The passage of thiobarbiturates and their oxygen analogs into brain
J Pharmacol Exp Ther
Influence of nutritional status on the pharmacokinetics and pharmacodynamics of pentobarbital
Drug Metab Dispos
Kinetics of phenobarbital in normal subjects and epileptic patients
Eur J Clin Pharmacol
Studies with stable isotopes II: Phenobarbital pharmacokinetics during monotherapy
J Clin Pharmacol
Clinical Pharmacokinetics of prozacin
Clin Pharmacokinet
Cited by (479)
Predicting the in vivo developmental toxicity of fenarimol from in vitro toxicity data using PBTK modelling-facilitated reverse dosimetry approach
2024, Toxicology and Applied PharmacologyComputer-aided biopharmaceutical characterization: Gastrointestinal absorption simulation
2023, Computer-Aided Applications in Pharmaceutical Technology: Delivery Systems, Dosage Forms, and Pharmaceutical Unit OperationsPredicting unpredictable human pharmacokinetics: case studies from the trenches of drug discovery
2023, Overcoming Obstacles in Drug Discovery and Development: Surmounting the Insurmountable-Case Studies for Critical ThinkingPhysiologically-based pharmacokinetic modelling of long-acting injectable cabotegravir and rilpivirine in pregnancy
2024, British Journal of Clinical Pharmacology