Influence of rifampicin on drug metabolism: Differences between hexobarbital and antipyrine

Abstract

Six healthy volunteers were treated with 1,200 mg of rifampicin daily for 8 days. Before and immediately afterward each received indocyanine green, hexobarbital, galactose, and antipyrine by intravenous infusion on 3 consecutive days. The plasma concentrations of the drugs were determined several times after infusion. The average elimination half-life of hexobarbital had decreased from 407 to 171 min and its metabolic clearance had increased almost threefold. In contrast, the average elimination half-life of antipyrine was virtually the same on both occasions (6.9 and 7.2 hr) and there was no change in metabolic clearance. In a tuberculous patient treated with rifampicin the antipyrine elimination rate was unaffected. Rifampicin did not influence indocyanine green clearance or galactose elimination capacity. Serum gamma glutamyl transferase was not affected but urinary D-glucaric acid excretion was increased during rifampicin treatment. The experiment with hexobarbital was repeated after 2 weeks in all subjects; half-lives and clearance values had returned to near control values. It appears that rifampicin is a selective inducer of oxidative drug metabolism in man.

Differential effects of enzyme induction on antipyrine metabolite formation.

“…Following treatment of healthy volunteers with rifampicin during 8 days a more than twofold increase in metabolic clearance of hexobarbitone and tolbutamide was observed (Zilly et al, 1975). However, when antipyrine and hexobarbitone were compared in the 0306-5251/82/030379-08 $01.00 same volunteers hardly any change in the elimination rate of antipyrine was observed, whereas hexobarbitone elimination rate had increased more than twice (Breimer et al, 1977). Similar observations have been made following halofenate and phenobarbitone Vesell & Passananti, 1975).…”

“…In order to detect enzyme induction in man antipyrine is frequently employed as a marker drug, whereby changes in half-lives or metabolic clearance values have been used as a measure of changes in enzyme activity (Vesell & Page, 1969;Roberts et al, 1976;Breimer et al, 1977;Kellermann & LuytenKellermann, 1977). However, antipyrine is metabolized via several pathways in man resulting in the formation of at least 4-phase I metabolites, that are excreted, at least partly, in a conjugated form in urine: 4-hydroxyantipyrine, norantipyrine, 3-hydroxymethyl-antipyrine and 3-carboxy-antipyrine (Baty & Price Evans, 1973;Brodie & Axelrod, 1950;Schuppel, 1966;Yoshimura etal., 1968Yoshimura etal., , 1971Zietz et al, 1978).…”

A comparative study of antipyrine and lignocaine disposition in normal subjects and in patients treated with enzyme‐inducing drugs.

“…Drugs which have been used to this purpose include antipyrine (Stevenson, 1977;Sotaniemi, Pelkonen, Ahokas, Pirttiaho & Ahlqvist, 1978;Vesell, 1979), aminopyrine (Vesell, Passananti, Glenwright & Dvorchik, 1975), phenylbutazone (O'Malley, Crooks, Duke & Stevenson, 1971), hexobarbitone (Breimer, Zilly & Richter, 1977), warfarin (Orme, Breckenridge & Brooks, 1972) and tolbutamide (Pond, Birkett & Wade, 1977). Since these agents are invariably characterized by a low hepatic extraction ratio and by non-saturable, flow-independent, restrictive elimination, it is generally preferable that estimated values of systemic blood clearance for these drugs be calculated from blood concentration data following intravenous administration (Wilkinson & Shand, 1975).…”

Enzyme induction and beta‐adrenergic receptor blocking drugs.

“…Understandably, there is a wide spectrum in the range and specificity of enzyme-inducing ability. Thus, enzymeinducing agents can either increase the enzyme activity of a large number of routes of metabolism, or be relatively selective for individual isoenzymes (Breimer et al, 1977).…”