Rifampicin is an inducer of hepatic drug metabolising enzymes. This results in interactions with several drugs including oral anticoagulants, hypoglycaemics, and contraceptives. Concurrent treatment with prednisolone and rifampicin is given when tuberculosis coexists with a disease that is sensitive to steroids, when the diagnosis is uncertain, or occasionally in the treatment of severe tuberculosis. Two patients with respiratory disease were treated with both drugs: their condition improved considerably after rifampicin was withdrawn. Seven patients were then studied to assess the effect of rifampicin on the pharmacokinetics of prednisolone. Overall, rifampicin increased the plasma clearance of prednisolone by 45% and reduced the amount of drug available to the tissues (area under the plasma concentration time curve) by 66%. The effectiveness of prednisolone may be considerably reduced when rifampicin and prednisolone are used in combination.

https://www.bmj.com/content/bmj/286/6369/923.full.pdf

Rifampicin reduces effectiveness and bioavailability of prednisolone.

Background and objective

Antipyrine has been widely used as a probe drug for human oxidative drug metabolism. To evaluate the role of antipyrine as a model drug, we have identified the cytochrome P450 enzymes involved in 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine formation.



Methods

We used the following methods for this study: (1) determination of enzyme kinetics for antipyrine metabolite formation in human liver microsomes, (2) inhibition studies with antibodies and inhibitors, and (3) formation of metabolites by stable expressed human P450 enzymes.



Results

Antipyrine biotransformation could be described by Michaelis-Menten kinetics: norantipyrine: maximum rate of metabolite formation (Vmax), 0.91 ± 0.04 nmol · mg−1 · min−1; Michaelis-Menten constant (Km), 19.0 ± 0.8 mmol/L; 4-hydroxyantipyrine: Vmax, 1.54 ± 0.08 nmol · mg−1 · min−1; Km, 21.2 ± 0.4 mmol/L; 3-hydroxymethylantipyrine: Vmax, 0.83 ± 0.04 nmol · mg−1 · min−1; Km, 39.6 ± 2.5 mmol/L. Antibodies against CYP3A4 inhibited the formation of 4-hydroxyantipyrine by 25% to 65%. LKM-2 antibodies (anti-CYP2C) caused a 75% to 100% inhibition of norantipyrine and a 58% to 80% inhibition of 3-hydroxymethylantipyrine formation. Sulfaphenazole inhibited the formation of 3-hydroxymethylantipyrine and norantipyrine by about 50%. Furafylline and fluvoxamine inhibited norantipyrine, 4-hydroxyantipyrine, and 3-hydroxymethylantipyrine formation by about 30%, 30%, and 50%, respectively. Ketoconazole reduced formation of norantipyrine, 3-hydroxymethylantipyrine, and 4-hydroxyantipyrine by up to 80%. Formation in stable expressed enzymes indicated involvement of CYP1A2, CYP2B6, CYP2C, and CYP3A4 in metabolite formation.



Conclusion

Antipyrine metabolites are formed by at least six hepatic cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, and CYP3A4). 4-Hydroxylation is mainly catalyzed by CYP3A4 and, to a lesser extent, by CYP1A2. The CYP2C subfamily contains the predominant enzymes for norantipyrine formation, and CYP1A2 is also involved. Formation of 3-hydroxymethylantipyrine is mediated by CYP1A2 and CYP2C9. Because several cytochrome P450 enzymes are involved in the formation of each metabolite, antipyrine is not well suited as a probe for distinct human cytochrome P450 enzymes.



Clinical Pharmacology & Therapeutics (1996) 59, 613–623; doi:

Antipyrine as a probe for human oxidative drug metabolism: Identification of the cytochrome P450 enzymes catalyzing 4‐hydroxyantipyrine, 3‐hydroxymethylantipyrine, and norantipyrine formation

Sex-related differences in the disposition of some analgesics, anxiolytics and hypnotics have recently been reported. With certain benzodiazepines, sex has been shown to be a more important determinant of variability in drug disposition than age, while with other benzodiazepines an age-related decline in clearance was more pronounced in men than women. In young healthy adults these sex-related differences in drug disposition were related to the phase of the menstrual cycle, oral contraceptive steroid administration, and variations in plasma concentrations of albumin, α1-acid glycoprotein, free fatty acids and sex hormones. While none of the sex-related differences so far reported necessitates the modification of a therapeutic dosage regimen, it is prudent that future protocols for pharmacokinetic studies should regard age, sex, the menstrual cycle and oral contraceptive steroids as potential sources of variability.

Sex-related differences in drug disposition in man.

Inter- and intraindividual variability in pharmacokinetics of most drugs is largely determined by variable liver function as described by parameters of hepatic blood flow and metabolic capacity. These parameters may be altered as a result of disease affecting the liver, genetic differences in metabolising enzymes, and various types of drug interactions, including enzyme induction, enzyme inhibition or down-regulation.

Assessment of liver metabolic function. Clinical implications.

In this issue of the Journal, Vesell and Penno evaluate two methods used to identify sources of interindividual pharmacokinetic variation. They emphasise the power of the antipyrine test (Vesell. 1979) in this regard. and criticise the method in­ volving multiple regression analysis as applied to antipyrine in some recent studies (Blain et aI., 1982; Fraser et aL 1976, 1977, 1979). The general ob­ jective of both approaches is to investigate quan­ titatively interindividual variation in oxidative drug-metabolising activity and to identify the fac­ tors and conditions contributing to it. Enzymatic oxidation in the liver is one of the most important processes in the disposition of many drugs and other foreign chemicals in animals and man. The rate of this process is often the limiting step in the elimination of a compound from the body and/or in the formation of active (reactive) metabolites. Large differences have been shown to exist be­ tween different species and among different indi­ viduals within one species in their capacity to ox­ idise drugs and other xenobiotics. This interspecies and interindividual variability is caused by genetic and environmental factors (Alvan. 1978: Breimer and Danhof. 1980; Conney. 1980; Sjoqvist and Von Bahe 1973; Vesell. 1977).

Interindividual variations in drug disposition. Clinical implications and methods of investigation.

Antipyrine is oxidised to three main metabolites in man. There is evidence that the different metabolites are products of different forms of cytochrome P-450. The effect of rifampicin administration for two weeks on the rates of formation of these metabolites was investigated in healthy volunteers. Rifampicin increased antipyrine clearance and shortened its half-life. Two weeks after stopping rifampicin the induction had largely been reversed. Clearance to all three metabolites was increased by rifampicin. Clearance to 3-hydroxymethylantipyrine was increased from 7.8±0.9 ml/min to 13.3±1.3 ml/min, to norphenazone from 5.8±0.6 ml/min to 19.3±2.1 ml/min and to 4-hydroxyantipyrine from 14.3±2.2 ml/min to 21.9±3.9 ml/min. Thus clearance to norphenazone was increased to a much greater extent than to either of the other two metabolites. It is concluded that this provides evidence for the involvement of at least two different forms of cytochrome P-450 in antipyrine metabolism in man.

V. Whitmarsh

Papers

Differential induction of antipyrine metabolism by rifampicin.