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

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 (V_ss) was calculated using model‐independent methods. The relation between V_ss and unbound drug fraction in plasma (f_u) was significantly correlated (V_ss = 0.844f_u + 0.119; r = 0.999, P < 0.01), indicating that the differences in f_u among these xanthine derivatives is mainly responsible for differences in V_ss. The decrease in V_ss 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