Interspecies Differences and Scaling for the Pharmacokinetics of Xanthine Derivatives

YOSHIMI TSUNEKAWA, TAKAAKI HASEGAWA, MASAYUKI NADAI, KENZO TAKAGI, Toshitaka Nabeshima

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Abstract— Pharmacokinetic characteristics of the new xanthine bronchodilators, enprofylline and 1‐methyl‐3‐propylxanthine (MPX), were investigated in mice, rats, guinea‐pigs, rabbits and dogs. The possibility of an interspecies pharmacokinetic scale was also evaluated. The concentration of these two drugs in plasma and urine was determined by HPLC. Pharmacokinetic parameters were calculated using model‐independent methods. The disappearance curves of the two drugs from plasma varied markedly among animal species. Interspecies differences in the plasma protein binding of each drug were observed for all animals in the study. Differences in the biotransformation of enprofylline and MPX were also confirmed among the various animal species: enprofylline is mainly excreted in an unchanged form in urine while MPX follows a non‐renal route of elimination. In all animals, the renal clearance for enprofylline was greater than the glomerular filtration rate, indicating active tubular secretion. Significant allometric relationships were seen between the values of total body clearance and steady state volume of distribution for both total and unbound enprofylline and species body weight, but similar correlations could not be recognized for MPX. Renal clearance of enprofylline was also closely correlated with species body weight, suggesting no interspecies difference with relation to affinity and/or capacity for the active tubular secretion mechanism of enprofylline. Our findings suggest that xanthine derivatives, including enprofylline, are mainly eliminated via the kidney, and an estimate of the basic pharmacokinetics in man can be obtained from data in experimental animals. 1992 Royal Pharmaceutical Society of Great Britain

Original languageEnglish
Pages (from-to)594-599
Number of pages6
JournalJournal of Pharmacy and Pharmacology
Volume44
Issue number7
DOIs
Publication statusPublished - 01-01-1992

Fingerprint

Xanthine
Pharmacokinetics
Kidney
Body Weight
Urine
Pharmaceutical Preparations
enprofylline
Bronchodilator Agents
Biotransformation
Glomerular Filtration Rate
Protein Binding
Blood Proteins
High Pressure Liquid Chromatography
Dogs
Rabbits

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Cite this

TSUNEKAWA, YOSHIMI ; HASEGAWA, TAKAAKI ; NADAI, MASAYUKI ; TAKAGI, KENZO ; Nabeshima, Toshitaka. / Interspecies Differences and Scaling for the Pharmacokinetics of Xanthine Derivatives. In: Journal of Pharmacy and Pharmacology. 1992 ; Vol. 44, No. 7. pp. 594-599.
@article{d1df52d68c014b91a0de594a5ae52971,
title = "Interspecies Differences and Scaling for the Pharmacokinetics of Xanthine Derivatives",
abstract = "Abstract— Pharmacokinetic characteristics of the new xanthine bronchodilators, enprofylline and 1‐methyl‐3‐propylxanthine (MPX), were investigated in mice, rats, guinea‐pigs, rabbits and dogs. The possibility of an interspecies pharmacokinetic scale was also evaluated. The concentration of these two drugs in plasma and urine was determined by HPLC. Pharmacokinetic parameters were calculated using model‐independent methods. The disappearance curves of the two drugs from plasma varied markedly among animal species. Interspecies differences in the plasma protein binding of each drug were observed for all animals in the study. Differences in the biotransformation of enprofylline and MPX were also confirmed among the various animal species: enprofylline is mainly excreted in an unchanged form in urine while MPX follows a non‐renal route of elimination. In all animals, the renal clearance for enprofylline was greater than the glomerular filtration rate, indicating active tubular secretion. Significant allometric relationships were seen between the values of total body clearance and steady state volume of distribution for both total and unbound enprofylline and species body weight, but similar correlations could not be recognized for MPX. Renal clearance of enprofylline was also closely correlated with species body weight, suggesting no interspecies difference with relation to affinity and/or capacity for the active tubular secretion mechanism of enprofylline. Our findings suggest that xanthine derivatives, including enprofylline, are mainly eliminated via the kidney, and an estimate of the basic pharmacokinetics in man can be obtained from data in experimental animals. 1992 Royal Pharmaceutical Society of Great Britain",
author = "YOSHIMI TSUNEKAWA and TAKAAKI HASEGAWA and MASAYUKI NADAI and KENZO TAKAGI and Toshitaka Nabeshima",
year = "1992",
month = "1",
day = "1",
doi = "10.1111/j.2042-7158.1992.tb05471.x",
language = "English",
volume = "44",
pages = "594--599",
journal = "Journal of Pharmacy and Pharmacology",
issn = "0022-3573",
publisher = "Pharmaceutical Press",
number = "7",

}

Interspecies Differences and Scaling for the Pharmacokinetics of Xanthine Derivatives. / TSUNEKAWA, YOSHIMI; HASEGAWA, TAKAAKI; NADAI, MASAYUKI; TAKAGI, KENZO; Nabeshima, Toshitaka.

In: Journal of Pharmacy and Pharmacology, Vol. 44, No. 7, 01.01.1992, p. 594-599.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Interspecies Differences and Scaling for the Pharmacokinetics of Xanthine Derivatives

AU - TSUNEKAWA, YOSHIMI

AU - HASEGAWA, TAKAAKI

AU - NADAI, MASAYUKI

AU - TAKAGI, KENZO

AU - Nabeshima, Toshitaka

PY - 1992/1/1

Y1 - 1992/1/1

N2 - Abstract— Pharmacokinetic characteristics of the new xanthine bronchodilators, enprofylline and 1‐methyl‐3‐propylxanthine (MPX), were investigated in mice, rats, guinea‐pigs, rabbits and dogs. The possibility of an interspecies pharmacokinetic scale was also evaluated. The concentration of these two drugs in plasma and urine was determined by HPLC. Pharmacokinetic parameters were calculated using model‐independent methods. The disappearance curves of the two drugs from plasma varied markedly among animal species. Interspecies differences in the plasma protein binding of each drug were observed for all animals in the study. Differences in the biotransformation of enprofylline and MPX were also confirmed among the various animal species: enprofylline is mainly excreted in an unchanged form in urine while MPX follows a non‐renal route of elimination. In all animals, the renal clearance for enprofylline was greater than the glomerular filtration rate, indicating active tubular secretion. Significant allometric relationships were seen between the values of total body clearance and steady state volume of distribution for both total and unbound enprofylline and species body weight, but similar correlations could not be recognized for MPX. Renal clearance of enprofylline was also closely correlated with species body weight, suggesting no interspecies difference with relation to affinity and/or capacity for the active tubular secretion mechanism of enprofylline. Our findings suggest that xanthine derivatives, including enprofylline, are mainly eliminated via the kidney, and an estimate of the basic pharmacokinetics in man can be obtained from data in experimental animals. 1992 Royal Pharmaceutical Society of Great Britain

AB - Abstract— Pharmacokinetic characteristics of the new xanthine bronchodilators, enprofylline and 1‐methyl‐3‐propylxanthine (MPX), were investigated in mice, rats, guinea‐pigs, rabbits and dogs. The possibility of an interspecies pharmacokinetic scale was also evaluated. The concentration of these two drugs in plasma and urine was determined by HPLC. Pharmacokinetic parameters were calculated using model‐independent methods. The disappearance curves of the two drugs from plasma varied markedly among animal species. Interspecies differences in the plasma protein binding of each drug were observed for all animals in the study. Differences in the biotransformation of enprofylline and MPX were also confirmed among the various animal species: enprofylline is mainly excreted in an unchanged form in urine while MPX follows a non‐renal route of elimination. In all animals, the renal clearance for enprofylline was greater than the glomerular filtration rate, indicating active tubular secretion. Significant allometric relationships were seen between the values of total body clearance and steady state volume of distribution for both total and unbound enprofylline and species body weight, but similar correlations could not be recognized for MPX. Renal clearance of enprofylline was also closely correlated with species body weight, suggesting no interspecies difference with relation to affinity and/or capacity for the active tubular secretion mechanism of enprofylline. Our findings suggest that xanthine derivatives, including enprofylline, are mainly eliminated via the kidney, and an estimate of the basic pharmacokinetics in man can be obtained from data in experimental animals. 1992 Royal Pharmaceutical Society of Great Britain

UR - http://www.scopus.com/inward/record.url?scp=0026625624&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026625624&partnerID=8YFLogxK

U2 - 10.1111/j.2042-7158.1992.tb05471.x

DO - 10.1111/j.2042-7158.1992.tb05471.x

M3 - Article

C2 - 1357141

AN - SCOPUS:0026625624

VL - 44

SP - 594

EP - 599

JO - Journal of Pharmacy and Pharmacology

JF - Journal of Pharmacy and Pharmacology

SN - 0022-3573

IS - 7

ER -