Structure‐pharmacokinetic Relationships among the N1, N3‐Alkylxanthines in Rats

Ruttikorn Apichartpichean, Takaaki Hasegawa, Masayuki Nadai, Takafumi Kuzuya, Toshitaka Nabeshima

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19 Citations (Scopus)


Abstract— The pharmacokinetics of four N3‐alkylxanthine and four N1‐methyl‐N3‐alkylxanthine derivatives has been investigated in rats after intravenous administration of the individual alkylxanthines. The concentration of N1, N3‐alkylxanthine in plasma and urine was determined by HPLC. A one‐compartment model adequately described the plasma concentration time data. The steady‐state volume of distribution (Vss) was calculated using model‐independent methods. The relation between Vss and unbound drug fraction in plasma (fu) was significantly correlated (Vss = 0.844fu + 0.119; r = 0.999, P < 0.01), indicating that the differences in fu among these xanthine derivatives is mainly responsible for differences in Vss. The decrease in Vss and increase in plasma protein binding with lipophilicity reflected a relatively constant tissue affinity. The total body clearance increased with lipophilicity with the exception of the first three lower congeners which were almost completely excreted unchanged in urine, mainly via active tubular secretion. Renal elimination was markedly reduced by the presence of a methyl group at the N1‐position. Renal clearance decreased with increasing lipophilicity, due to increased tubular reabsorption whereas non‐renal (hepatic) clearance increased with increasing lipophilicity. 1991 Royal Pharmaceutical Society of Great Britain

Original languageEnglish
Pages (from-to)262-269
Number of pages8
JournalJournal of Pharmacy and Pharmacology
Issue number4
Publication statusPublished - 04-1991
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science


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