Biotransformation of drugs in man

Chando TJ, Everett DW, Kahle AD, Starrett AM, Vachharajani N, Shyu WC, Kripalani KJ, Barbhaiya RH. Biotransformation of irbesartan in man. Drug Metab Dispos 1998 26 408 17. 

Several research groups have demonstrated that species differences in the biotransformation of drugs with diverse but known in vivo metabolite patterns, could be reproduced with hepatocytes. Hepatocytes from diverse species like rats, rabbits, dogs, monkeys and man have been used to study the biotransformation of tolbutamide 37), amphetamine 38), ketitofen 39) and diazepam 40). These and other comparative studies again demonstrate that in general extrapolation of data obtained with cellular fractions, hepatocytes or intact animals from one species to another species is not possible, and stresses the need for the use of target-animals for risk-assessment purposes. 

Racemic warfarin (65), a vitamin K antagonist, has been used for decades both as an oral anticoagulant in man and as a rodenticide. The metabolism of this drug has been found to be substrate-enantioselective 9S-warfarin is considered as more active than the 9R-antipode. In mammalian systems, warfarin undergoes a stereoselective reduction of the ketonic side chain [176,177], affording mainly the 9R,llS-alcohol (71), but the major biotransformation route involves substrate-enantioselective aromatic hydroxylations at 4 -, 6-, 7- or 8-positions... 

When stereoisomers are biotransformed by a variety of pathways, differences in the susceptibility of the separate isomers to these pathways result in stereoselectivity for their metabolite patterns. For example, 5-warfarin is oxidized to form primarily 7-hydroxy-5-warfarin, whereas the R enantiomer predominantly undergoes hydroxylation in the 6-position.f Oxazepam glucuronidation is 3-3.4 times higher for the S isomer compared to the R isomer in man and dogs. Biotransformation may generate an additional chiral center in the drug structure and result in diastereo-meric metabolites with markedly different disposition characteristics. 

In a study by Burns et al 9 in which the plasma levels of meperidine hydrochloride were measured after intravenous injection in man, it was inferred that metabolism occurs at a rate varying from 10 to 20 per hour (17 average) in ten different subjects. No accumulation of the drug after repeated administration was found in this study and only 5 of the drug was found to be excreted unchanged in the urine. Plotnikoff et al3l determined that the biotransformation products of meperidine hydrochloride excreted in human urine are normeperidine (I), meperidinic acid (II), nor-... 

A typical example of an effective bioprecursor prodrug is given by the anti-inflammatory drug sulindac. Sulindac, di-5-fluoro-2-methyl-l-[p-(methylsulfinyl) benzylidene] indene-3 acetic acid is a non-steroidal anti-inflammatory agent having a broad spectrum of activity in animal models and in man. The two quantitatively significant biotransformations undergone by sulindac in laboratory species and... 

Sattler M, Guengerieh FP, Yun CH, Christians U, Sewing KF (1992) Cytoehrome P-450 3A enzymes are responsible for biotransformation of FK506 and rapamycin in man and rat. Drug Metab Dispos 20 753-761... 

Desmethylcyproheptadine 10,11-epoxide, a biotransformation product of the antihistaminic and antiserotoninergic drug, cyproheptadine inhibited proinsulin and insulin biosynthesis and insulin release in isolated rat pancreatic islets (Chow et al. 1989). Measurement of (pro)insulin (proinsulin and insulin) synthesis using incorporation of H-leucine showed that desmethylcyproheptadine epoxide, desmethylcyproheptadine and cyproheptadine epoxide were 22,10, and 4 times, respectively, more potent than cyproheptadine in inhibiting hormone synthesis. In man, there was no evidence for metabolic alteration at the tricyclic ethylene bridge (C-10, C-11), whereas dog, cat, and rat all metabolise the drug, at least in part, at this site (Porter et al. 1974). A minor N-oxide conjugate as a metabolite of cyproheptadine has been found in man (Johnson et al. 1962). 

Biotransformation studies of these compounds were carried out both in vitro , by incubation with rat liver microsomes, and in vivo , in rat and, for clinically used drugs, also in man. The original hypothesis of the involvement of an "epoxide-diol metabolic pathway common to all the listed drugs has been confirmed be means of chromatographic and mass spectrometric techniques (17, 22). 

The second caveat is that, in order to accurately predict hepatic clearance, the correct in vitro system must be chosen. If the candidate drug is primarily oxidatively metabolized, then liver microsomes will be sufficient. However, if the potential for non-microsomal biotransformation exists, then a different in vitro system, such as hepatocyte suspensions, should be used. In the illustration above, it turned out, as far as clearance of Compound X is concerned, man is specifically like a rat, and unlike a dog. 

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