Pharmacodynamics and Conjugation

In a number of cases the transferase enzymes metabolize compounds to active species. Morphine is a highly potent opioid analgesic (Figure 7.26) and is metabolized by glucuronidation of both its hydroxyl functions in both the gastrointestinal tract and the liver. Glucuronidation of the 6-position to form morphine-6-glu-curonide gives a compound that is also active [25]. Given systemically, the metabolite is twice as potent as morphine itself. When administered intrathecally the compound is approximately 100-fold more potent than the parent morphine.

Fig. 7.26 Structure of morphine, which is metabolized to a more active opioid analgesic by glucuronidation at the 6 position.

Unlike morphine, minoxidil [26] is not active itself but is metabolized by hepatic sulphotransferases to minoxidil N-O sulphate (Figure 7.27).

Minoxidil sulphate is a potent activator of the ATP-modulated potassium channel and thereby relaxes vascular smooth muscle to give a resultant antihypertensive effect. The actual sulphate metabolite is a relatively minor metabolite, the principal metabolite being the N-O glucuronide. The discovery of minoxidil illustrates the caution which should be applied to screening compounds solely in vitro. Occasionally in vivo experiments will provide significant advances as a result of the metabolism of novel active agents.


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Pharmacokinetics and Metabolism in Drug Design 99 Edited by D. A. Smith, H. van de Waterbeemd, D. K. Walker, R. Mannhold, H. Kubinyi, H. Timmerman I

Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-30197-6 (Hardcover); 3-527-60021-3 (Electronic)

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