Current Drug Metabolism, Vol. 1, No. 4, 2000
Sense
and Nonsense in the Prediction of Drug-Drug Interactions.
Pp. 305-331.
Jiunn H. Lin
Experimental
Methods for Studying Drug uptake in the Head and Brain. Pp. 333-356.
K.A. Foster
and M.S. Roberts
The Biotransformation of Nitrogen Containing Xenobiotics to Lactams. Pp. 357-389.
S. Vickers and
S. L. Polsky
Prostaglandin
H Synthases and their Importance in Chemical Toxicity. Pp. 391-404.
Christoph
Vogel
[Back to top] Sense and Nonsense in the Prediction of Drug-Drug Interactions.
Jiunn H. Lin
Drug interactions are always a major concern in
medicine and within the pharmaceutical industry. Fatal drug interactions have
been reported, and several prominent drugs have been withdrawn from the market
because of serious adverse reactions related to drug interactions. Therefore,
drug interactions represent not only a medical problem for clinicians, but also
an economic loss for pharmaceutical companies. Today, many pharmaceutical
companies are predicting potential interactions of new drug candidates in an
attempt to minimize such losses and to more effectively safeguard the welfare of
patients.
Can in vivo drug interactions be predicted accurately from in vitro metabolic studies? Should the prediction be qualitative or quantitative? These are the fundamental questions that industrial drug metabolism scientists must confront daily. Prediction of in vivo drug interactions from in vitro metabolic data is highly controversial, because of the complexities of factors that are involved in drug interactions. Some scientists believe that quantitative prediction of drug interaction is possible, whereas others are less optimistic, and believe that quantitative prediction is extremely difficult, if not impossible. The purpose of this review is to present and discuss the technical problems inherent in estimating in vitro Ki values and in measuring inhibitor concentration at the active-site of enzymes. Theoretic considerations are briefly reviewed, and representative examples are drawn from literature to illustrate the sense and nonsense in predicting in vivo drug interactions.
[Back
to top] Experimental
Methods for Studying Drug uptake in the Head and Brain.
K.A. Foster and M.S. Roberts
A number of techniques have been developed to study the disposition of drugs in the head and, in particular, the role of the blood-brain barrier (BBB) in drug uptake. The techniques can be divided into three groups: in-vitro, in-vivo and in-situ. The most suitable method depends on the purpose(s) and requirements of the particular study being conducted. In-vitro techniques involve the isolation of cerebral endothelial cells so that direct investigations of these cells can be carried out. The most recent preparations are able to maintain structural and functional characteristics of the BBB by simultaneously culturing endothelial cells with astrocytic cells. The main advantages of the in-vitro methods are the elimination of anaesthetics and surgery. In-vivo methods consist of a diverse range of techniques and include the traditional Brain Uptake Index and indicator diffusion methods, as well as microdialysis and positron emission tomography. In-vivo methods maintain the cells and vasculature of an organ in their normal physiological states and anatomical position within the animal. However, the shortcomings include renal and hepatic elimination of solutes as well as the inability to control blood flow. In-situ techniques, including the perfused head, are more technically demanding. However, these models have the ability to vary the composition and flow rate of the artificial perfusate. This review is intended as a guide for selecting the most appropriate method for studying drug uptake in the brain.
[Back
to top] The
Biotransformation of Nitrogen Containing Xenobiotics to Lactams.
S. Vickers and S. L. Polsky
The metabolism of nitrogen heterocyclics may lead to lactam formation. In early studies on xenobiotic metabolism lactams were identified as metabolites of nicotine, cyproheptadine, tremorine and prolintane. Now, because of the increasing availability of powerful analytical techniques, there are many instances of lactams being identified as metabolites. Lactam metabolites are formed from either iminium ions or carbinolamines. These two intermediates may have distinct mechanisms of formation but they can interconvert. There is evidence that the iminium ions are oxidized to lactams by aldehyde oxidases (cytosolic molybdenum hydroxylases). The tissue distribution and enzyme activities of aldehyde oxidase have been studied in several animal species. However, it is also known that iminium ions can undergo spontaneous hydrolysis to the corresponding carbinolamine. If the latter is stable it may undergo oxidation by cytochrome P-450 to form the lactam. Thus, species differences in lactam formation might be caused by differences in the concentrations of either cytochrome P450 isozymes or aldehyde oxidases. It appears that lactam formation is an end stage in the metabolism of N -heterocycles in that it is unlikely that the lactam will undergo hydrolysis to the corresponding amino acid. Such amino acids probably arise from the amino aldehydes that may be produced from ring opening of unstable carbinolamine intermediates. When microsomal preparations are incubated with the appropriate substrate in the presence of sodium cyanide the iminium ion may be trapped to produce a cyano compound. Such reactions have led to the proposal that iminium ions might react with nucleophilic sites of cellular macromolecules and so contribute to both the pharmacology and toxicology of N-heterocyclic compounds. Other pathways for the formation of lactam metabolites involve the internal cyclization of precursor metabolites, e.g. the self-condensation of an aldehyde group (formed during metabolism) with a neighboring amide group. However, spontaneous ring closures of amino acids to form lactams seem unlikely since it would be anticipated that the amino acid residue would exist as a stable zwitterion under physiological conditions. Thus, it is unlikely that lactams will undergo futile metabolism via hydrolytic ring opening followed by ring closure. Under extreme conditions such unanticipated ring closures may occur and the conditions of metabolite isolation may contribute to the occurrence of artifacts.
[Back to top] Prostaglandin H Synthases and their Importance in Chemical Toxicity.
Christoph Vogel
The
metabolism of a xenobiotic is an important stage resulting in its toxification (bioactivation)
or detoxification. The most common reaction is the oxidation catalyzed by the
cytochrome P450 (CYP) enzyme system. An alternate enzyme for chemical oxidation
is the prostaglandin H synthase (PGHS) also known as cyclooxygenase (COX). The
PGHS is the initial enzyme in arachidonate metabolism and formation of
prostanoids such as prostaglandins (PG), prostacyclins, and thromboxanes.
However, 25 years ago it was found that during the reduction of the endogenous
substrate, hydroperoxy-endoperoxide (PGG2) to hydroxy-endoperoxide
(PGH2), the PGHS enzyme is capable to “co-oxidize” chemicals. In
this reaction, a broad spectrum of chemicals can serve as electron donors such
as phenolic compounds, aromatic amines, and polycyclic aromatic hydrocarbons. In
contrast to numerous CYP enzymes in liver, the PGHS is an alternate enzyme for
xenobiotic metabolism in extrahepatic tissues. In respect of tissue
distribution, PGHS can play an essential role in the bioactivation of e.g.
procarcinogenic chemicals in certain target tissues that possess low CYP
monooxygenase activity.
Two PGHS isozymes have been identified: PGHS-1 and PGHS-2, which have very similar kinetic properties, but differ in regard to expression and regulation. In recent studies it was shown that not only endogenous stimuli but also drugs and environmental chemicals can activate PGHS-2 expression. Therefore the PGHS enzymes provide two interesting aspects for pharmacology and toxicology: a) the co-oxidation of chemicals and b) the altered synthesis of prostanoids after exposure to certain xenobiotics which can be essential for their ultimate toxicity.