Rifampicin, a keystone inducer of drug metabolism: From Herbert Remmer's pioneering ideas to modern concepts

In 1972, Herbert Remmer's group at the University of Tubingen had developed a micro method to assess cytochrome P450 contents and activities of drug metabolising enzymes in needle biopsies from human liver. Upon application of this method to patients receiving different kinds of drug therapy, Herbert Remmer was the first to describe that total human hepatic cytochrome P450 was markedly elevated by the new anti-tuberculosis drug rifampicin. Similar observations were made for the antimycotic clotrimazol. In 1975, Herbert Remmer's group described the unique species difference that induction of cytochrome P450 by rifampicin did not occur in the rat. After the first clinical reports of impaired effectiveness of oral contraception in persons treated with rifampicin, studies at Herbert Remmer's institute showed a 4-fold increase, after repetitive rifampicin administration to humans, in the ability of hepatic microsomes to ortho-hydroxylate the contraceptive estrogen ethinylestradiol, compared to microsomes from untreated normal subjects. Subsequent pharmacokinetic investigations were compatible with this induction of the estrogen-2-hydroxylase by rifampicin and provided a rational explanation for the classical drug interaction between rifampicin and oral contraceptives. These early studies, in the 1970s in Tubingen, were followed by further developments. It was realized that the cytochrome P450 isoenzyme 3A4 (CYP3A4) is the major CYP isozyme in the human liver metabolizing a variety of xenobiotics and endobiotics, being also responsible for the 2-hydroxylation of ethinylestradiol. The inducibility of CYP3A4 by barbiturates and rifampicin explains the effects of inducers to enhance the clearance of ethynylestradiol and thereby to reduce the effectiveness of oral contraceptives, rifampicin being one of the most potent inducers of human CYP3A4 gene expression. Since 1998, novel "orphan" members of the nuclear hormone receptor superfamily were cloned from mouse, rat, rabbit, and human origin. These so-called pregnane X receptors (PXR), across species, are activated by inducers of CYP3A4 expression. It now appears that PXR is a key mediator of complex induction processes of xenobiotic processing enzymes, which are triggered by rifampicin and other inducers. Studies of the structure and substrate affinities of PXR have provided the rational explanation of the unique species difference of rifampicin induction between humans and rats that was first described by Herbert Remmer.