Correlation between the in vivo Metabolism of Hexobarbital and Antipyrine in Rats with a Portacaval Shunt

Abstract

To investigate how hepatic malfunction affects the disposition of hexobarbital (HB), an intermediate ‘high-clearance’ compound, and antipyrine (AP), a low-clearance compound, as well as the correlation between the rates of elimination of these drugs, their pharmacokinetics, were studied in control rats (n = 8) and in rats with a portacaval shunt (PCS; n = 9). Blood concentrations of parent drugs were measured, and urinary excretion of the following metabolites was determined: 3-hydroxymethylantipyrine (HMA), 4-hydroxyantipyrine and norantipyrine as primary metabolites of AP, and 3’-hydroxyhexobarbital (OH-HB) and 3’-ketohexobarbital (K-HB) as primary metabolites of HB.Blood elimination half-lives of AP and HB were more than four times longer in PCS rats than in control rats, increasing from 63.7 ± 3.9 to 291 ± 66 min, and from 20.1 ± 1.8 to 84.2 ± 7.6 min, respectively. Intrinsic clearance of HB (CL_{int, HB}) was 167 ± 19 ml/min/kg in controls and 27 ± 4 ml/min/kg in PCS rats (CLp_int, _HB). Intrinsic clearance of AP (CL_Mnt, ap) in control rats was 15.1 ± 0.7 ml/min/kg and 5.9 ± 0.7 ml/min/kg in PCS rats (CL_{pcs, AP}). PCS reduced clearance for production of metabolites (CL_Mn) of AP by 50%, but CL_Mn of HB metabolites was decreased by more than 80%. The CL_{int, AP}, CL_int,HB, CL_pcs,HB, CL_pcs,AP, and CL_Mn data were correlated. Total clearance correlated better in PCS rats than in control rats: r = 0.77 versus r = 0.10, respectively, thus suggesting a decrease in substrate selectivity under pathological conditions. CL_OH-HB+K-HB, reflecting the major metabolic pathway of HB, correlated most closely with CL_HMA in PCS (r = 0.91). Therefore, the underlying metabolic conversions of HB and AP may be mediated by the same or very similar forms of cytochrome P-450. Our results suggest that the predictive value of the model substrate approach is valid under pathological conditions.

Relationship between the metabolism of antipyrine, hexobarbitone and theophylline in man as assessed by a ‘cocktail’ approach.

“…The three substrates were administered simultaneously in a cocktail approach to overcome the contribution of intraindividual differences in drug oxidation. This experimental strategy has proved to be feasible in previous studies in rats and in man (Van der Graaff et al, 1983a;Teunissen et al, 1985Teunissen et al, , 1986. For the substrates used in the present study it was assumed that complete absorption after oral administration took place and also that oral clearance equalled intrinsic clearance.…”

“…Assays of drugs and metabolites AP and HB in plasma were simultaneously determined in both experiments by applying a gas chromatographic assay described by Van der Graaff et al (1983a) with some modifications.…”

“…Hexobarbitone (HB) and theophylline (TH) are also frequently applied as model substrates and it has been suggested that these two substrates might be used as markers of particular cytochrome P-450 isozymes ( Van der Graaff et al, 1983a;Kappas et al, 1976). In rats the feasibility of an approach in which such substrates are administered simultaneously, in order to assess common pathways in metabolic oxidation, has been investigated and proved to be successful ( Van der Graaff et al, 1983a,b).…”

“…Antipyrine (AP) is one of the most widely used model substrates for the assessment of the drug oxidizing enzyme activities (Vesell, 1979) and there is evidence that different isozymes are responsible for the formation of the main metabolites of AP Danhof et al, 1979). Hexobarbitone (HB) and theophylline (TH) are also frequently applied as model substrates and it has been suggested that these two substrates might be used as markers of particular cytochrome P-450 isozymes (Van der Graaff et al, 1983a;Kappas et al, 1976). In rats the feasibility of an approach in which such substrates are administered simultaneously, in order to assess common pathways in metabolic oxidation, has been investigated and proved to be successful (Van der Graaff et al, 1983a,b).…”

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“…Aminopyrine Ndemethylase enzyme is categorized as N-dealkylation reaction, which belongs to one of the oxidation processes in the phase I hepatic drug metabolism reaction 9 . Aminopyrine metabolism in rats is primarily metabolised in vivo by the same or closely related major phenobarbital-inducible cytochrome P-450 isoenzymes with hexobarbital but not with the 3-methylcholanthrene-inducible cytochrome P-450 isoenzymes 10 .…”