Conjugative drug metabolism in liver transplant patients.
Raman VenkataramananK KalpM. RabinovitchRafael E. CuellarR J PtachcinskiLewis TepermanL MakowkaG J BurckartDavid H. Van ThielThomas E. Starzl
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Most drugs undergo biotransformation before excretion by renal, biliary or other routes. The main purpose of metabolism is to make the drug, which is usually lipophilic, more water soluble. Metabolic reactions, depending upon the end product formed, can be classified as functionalisation (phase I) or conjugation (Phase II) reactions. Phase I metabolic reactions include oxidation, reduction and hydrolysis; while phase II processes are glucuronidation, sulfation, methylation, acetylation and mercapture formation. Cytochrome P-450 isozymes play a central role in metabolism of great majority of xenobiotics, as well as some endogenous substances. Many drugs can inhibit, induce and alter relative amounts of different P-450 enzymes; therefore, possibilities of drug-drug interactions exist in that one drug can influence biodisposition of another with potential clinical implications. One drug can inhibit metabolism of another, leading to excessive accumulation and toxicity. Alternatively, one drug can stimulate or induce metabolism of another drug resulting in subtherapeutic plasma levels of the later.
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1. Single sample clearance estimates, CL, were calculated for seven drugs employed as probes of human hepatic drug-metabolizing enzymes. Clearance estimates were calculated in healthy young adult male volunteers either taking no pretreatment, or taking phenobarbitone (PB) 100 mg nightly for 3 nights. This intermittent regimen (3 nights on, followed by 4 nights off) was repeated for at least 3 consecutive weeks prior to challenge with an individual probe.2. Valproic acid was selected as a probe of both peroxisomal and microsomal β-oxidase activity; antipyrine, phenytoin, quinidine, and carbamazepine were selected as probes of hepatic mixed-function oxidases (MFO), and lorazepam as a probe for UDP-glucuronosyl transferase activity.3. Clearances of all probes except lorazepam, theophylline and phenytoin were approximately 20-30% faster in PB-treated than in control subjects; however, only in the case of carbamazepine did the increased clearance approach statistical significance. Neither phenytoin nor theophylline clearances were increased by PB.4. A clearance index (probe CL for PB-treated subjects divided by probe CL for untreated subjects) was calculated for each probe, and an ordinal transformation of the log of the resultant ratio was plotted for each probe giving rise to a ‘handprint' of the effect of PB on drug-metabolizing activity.
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As one of natural drugs, garlic with multiple effective pharmacological component has been widely used in clinical therapy. However, its long-term application may induce or inhibit hepatic drug metabolic enzymes and drug transporters, which result in the alteration of drug metabolism and the occurrence of drug-drug interaction.
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In a study employing hepatic microsomes from rats, estradiol-17β, testosterone, androsterone, progesterone, and hydrocortisone inhibited competitively the oxidation of ethylmorphine and hexobarbital. Inhibitor constants for each steroid were the same whether ethylmorphine or hexobarbital served as substrates. Results are consistent with the concept that certain drugs and steroids are alternative substrates for a common microsomal mixed function oxidase system. The inhibitory effects of steroids on chlorpromazine metabolism were both qualitatively and quanitatively different from those observed when ethylmorophine and hexobarbital metabolism were studied. Not only were the steroids less potent inhibitors of chlorpromazine oxidation, but inhibition was not competitive.
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