Biotransformation and toxicity of inhalational anaesthetics

0 Department of Anesthesiology, Hiroshima University School of Medicine , Hiroshima, Japan Anaesthetics are "xenobiotics," that is chemical compounds that are foreign to the human body. Volatile anaesthetics are distributed through the lung and blood to various organs. They can be metabolized by specific enzyme systems which have high activity in the liver but which are also present in the kidney and other organs. The processes of distribution and elimination of drugs and their metabolites have been studied for each anaesthetic, t Most anaesthetics are lipophilic which facilitates penetration of membrane barriers. The water/gas or blood/gas ratios and oil/gas or lipid/gas ratios of inhalational anaesthetics play an important role in their absorption and accumulation in the body. The volatile anaesthetic with the lowest solubility in the body is considered to be sevoflurane which has been recently placed on the market in Japan. Its water/gas or blood/gas ratio is similar to that of nitrous oxide, but the oil/gas or fat/gas ratio differs from that of nitrous oxide. It has, theoretically, a lower absorption and accumulation in the body. Metabolism of a drug, in general, may lead to the formation of a metabolite that is much less toxic than the parent compound, but in some cases the toxicity is enhanced by metabolism. Elimination of drug and its metabolites usually takes place in the urine, bile (faeces), and expired gas. This paper describes the current concept of biotransformation and toxicity of inhalational anaesthetics (Table I). - Biotransformation The enzymatic reactions involved in hepatic drug metabolism can be classified into phase I and phase I! reactions, that is, oxidation or reduction (phase I) and conjugation or synthesis (phase 1I) (Table II). An important aspect is the properties of the enzymes that catalyze the metabolic conversions of drugs. Many of these enzymes are located in the microsome, that is in the membrane framents of the endoplasmic reticulum. In particular the enzymes of the oxidation system, such as cytochrome P450, are present in the microsome although some are found in the cytosol and mitochondria. The membranes of rough and smooth endoplasmic reticulum, which are connected, are considered to contain the cytochrome P450 enzyme system. Singer's membrane model is well established and contains various kinds of enzymes. The membrane of the endoplasmic reticulum of liver cells resembles this schematic figure which shows the microsomal monooxidase enzyme system containing cytochrome P450 (Figure I). Flavoproteins, bs and other enzymes concerned with electron transport are located in the membrane of endoplasmic reticulum near cytochrome P450. The cytochrome P450 oxidation system is an electrontransport system containing terminal oxidase haemprotein and is associated primarily with membranes of the endoplasmic reticulum. Cytochromes, which are haemcontaining proteins, are termed P450, P448 or others depending on the wave length of the maximal absorption spectrum of the reduced form after carbon monoxide binding. However, in general, these enzymes are called cytochrome P450. It is known that P450 system contains enzymes which are induced by repeated administration of phenobarbitone and that the enzymes of the P448 system are induced by repeated administration of methylcholanthrane. Figure 2 shows the differences of wave-length of the absorption spectrum of microsomes before and after repeated administration of phenobarbital or methylcholanthrane (3-MC). It is speculated that cytochrome P450 contains two drug-binding sites. Biotransformation o f h a l o t h a n e (Figure 3) Phase I reactions We investigated the oxidative (aerobic)2-5 and reductive (anaerobic)6 dehalogenation of halothane by the cytochrome P450 oxidation system. Two anaerobic volatile metabolites, chlorodifluoroethylene (CDE) and chlorotrifluoroethane (CTE) in the expired gas, 7 and an aerobic metabolite of trifluoroacetic acid (TFA) and fluoride ion were found in the bile, saliva, blood and urine during and following administration of halothane. 8-,3 Also, the effects of enzyme-inducing drugs, such as phenobarbitone and other barbiturates which are used clinically, on aerobic and anaerobic dehalogenation of Morio etal.: BIOTRANSFORMATION AND TOXICITY OF INHALATIONAL ANAESTHETICS TABLEI Solubility of anaesthetics FIGURE I Microsomal enzyme model modified Singer's membrane model by Y. Yoshida. The shaded portion indicates hydrophobic. With permission from author and publisher. TABLEII Enzymatic reactions Pathwaysof drug metabolism Wave-length of absorption spectrum of P450 and P448. halothane w e r e i n v e s t i g a t e d . 4 T h e greatest i n d u c t i o n was seen after p h e n o b a r b i t o n e and t h i o p e n t o n e and t h i a m y l a l produced s i g n i f i c a n t l y m o r e induction than in the control or after p e n t o b a r b i t o n e and s e c o b a r b i t o n e . Phase H reactions T h e final step in the m e t a b o l i s m o f a f o r e i g n c o m p o u n d i n v o l v e s c o n j u g a t i o n with a w a t e r - s o l u b l e m e t a b o l i t e . T h e most c o m m o n c o n j u g a t i o n is g l u c u r o n i c acid adduct catalyzed by U D P - g l u c u r o n y l transferase, w h i c h is localized in the e n d o p l a s m i c r e t i c u l u m . C y t o s o l i c sulfotransferases catalyze the sulfation reaction o f a l c o h o l , bile acids, and a w i d e range o f p h e n o l i c c o m p o u n d s . Glutathione, a cysteine c o n t a i n i n g tripeptide, is c o n j u g a t e d to " - , . . Sodalime U / [ HCI 9 "~ l y F Br e . . ~ "P'~re~ ~'-c'-~'_~ / CANADIAN JOURNAL OF ANAESTHESIA O. H H F B r = C-C-C-S-C-C-H (N-acetyI-S-(2-bromoHO' ~-II~I ' 1~ CI 2-.ch!oro-I.l-di.fluoro [Urine] C=O emyl/-L-cyste,ne, F O H H F H H H ( D i f l u o r o c h l o r o e t h y l e n e ) [ E x p | r t ~ l Oas] (Trifluoroaeetic acid) FIGURE 3 Biotransformation of halothane. xenobiotics by its free thiol group. This reaction is catalyzed by glutathione-s-transferase, but can occur, although at a slower rate, in its absence. Glutathione-stransferases ensure that these very reactive molecules are rapidly conjugated with glutathione, thus preventing toxic reactions. Under adverse conditions, the available glutathione substrate may be rapidly depleted so that potentially toxic compounds are accumulated. Factors affecting hepatic drug metabolism (enzyme induction) Clinical effects of enzyme induction only become apparent when the rate-controlling step in detoxication or elimination is affected. However, enzyme induction may have major effects in enhancing the metabolism of xenobiotics to toxic intermediates. The enzyme inducers reported in the literature are shown in the Table III. The rate and manner in which an individual metabolizes drugs are determined, in part, by genetic factors but these are rarely apparent unless they result in toxicity. TABLEIII (...truncated)