Enzyme Induction CYP3A4 and Drug Design

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Although largely an adaptive response and not a toxicity enzyme induction, the interaction of cytochrome P450 in particular, with a drug is undesirable, as it may affect the efficacy of the drug or co-administered drugs. The number of clinically used drugs which induce P450 enzymes is, in fact, quite limited. However, in certain disease areas (AIDS, epilepsy) many of the drugs used, whether for primary or secondary indications, have the potential for enzyme induction. Induction is often seen pre-clinically, due to the elevated dose levels used, but this potential rarely transfers to the clinical situation [46].

No clear SAR emerges for induction, nor are any particular groups or functions implicated as shown by the diverse structures of the known CYP3A4 inducers (Figure 8.29). Structures are diverse but most are lipophilic as defined by a positive calculated log P value.

A critical factor in P450 induction in the clinic, based on drugs known to induce P450, is the question of dose size. The major inducible form of P450 in man is CYP3A4. The drugs that induce CYP3A4 are given in high doses, often around 500-1000 mg day-1 (Table 8.3). These result in total drug concentrations in the

Tab. 8.3 Dose, total and free plasma concentrations for clinical CYP3A4 inducers.



Cp free

(mg day-1)











































Fig. 8.29 Structures of known clinical CYP3A4 inducers: nevirapine (A), troglitazone (B), phenobarbitone (C), efavirenz (D), probenicid (E), phenytoin (F), moricizine (G), felbamate (H), rifampicin (I) and carba-mazepine (J).

Fig. 8.29 Structures of known clinical CYP3A4 inducers: nevirapine (A), troglitazone (B), phenobarbitone (C), efavirenz (D), probenicid (E), phenytoin (F), moricizine (G), felbamate (H), rifampicin (I) and carba-mazepine (J).

10-100 |M range or approximately an order of magnitude lower than that expressed as a free drug concentration (Table 8.3). The concentrations equate closely to the therapeutic plasma concentrations presented in Table 8.3. These data both reflect the relatively weak affinity of the inducing agents and the need for high concentrations or doses. The high clinical concentrations reflect the weak potency of the drugs. For instance the Na+ channel blockers have affinities of 3, 9 and 25 |M (moricizine, phenytoin and carbemazepine, respectively). With the anti-infectives there is the need to dose to the IC95 level or greater. Thus, although efavirenz is a potent inhibitor of wild-type RT HIV (Ki = 3 nM), there is a need to go to higher concentrations to reach the IC95 for the virus and also to treat for possible mutants.

In contrast to these concentrations many clinically-used drugs, which are non-in-ducers are effective at doses up to two orders of magnitude lower. The need for high doses has other undesirable complications. As outlined above dose size is important in toxicity and enzyme inducers show a high level of adverse drug reactions affecting such organs and tissues as the liver, blood and skin (Table 8.4).

This statement is somewhat at odds with the conventional view that idiosyncratic toxicology is dose-size independent. Idiosyncratic reactions are thought to result from an immune-mediated cell injury triggered by previous contact with the drug. The toxicity may appear after several asymptomatic administrations of the com-

8.13 Enzyme Induction (CYP3A4) and Drug Design 1119 Tab. 8.4 Clinical toxicities and side-effects of P4503A4 inducers.


Aplastic anaemia, agranulocytosis,

skin rash, hepatitis


Agranulocytosis, skin rash, hepatitis


Shock, haemolytic anaemia, renal failure


Aplastic anaemia, agranulocytosis,

skin rash


Hepatic toxicity


Hepatitis, skin rash


Hepatitis, skin rash




Aplastic anaemia, hepatic necrosis


Aplastic anaemia

pound (sensitization period) and is not perceived as dose dependent. For instance when the relationship between the occurrence of adverse side-effects and the use of anti-epileptic drugs was examined, there was no definite dose- or serum concentration-dependent increase in the incidence of side-effects. In fact on closer examination idiosyncratic toxicology and dose size seem firmly linked. Not in the terms of a single drug used over its clinical dose range as above, but that adverse reactions occur more often with high dose drugs. Aside from the examples above an excellent example is clozapine and its close structural analogue olanzapine (Figure 8.30). Clozapine is used clinically over the dose range of 150-450 mg and its use is associated with agranulocytosis. Olanzipine is used clinically at 5-10 mg and is associated with a negligible risk of agranulocytosis. As outlined in Section 8.4 both compounds could potentially be activated to form reactive intermediates such as nitrenium ions.

The impact of reducing dose size by either intrinsic potency increases or optimizing pharmacokinetics is also critical in avoiding P450 induction. An example of this is the anti-diabetic compound troglitazone (Figure 8.31). This is used at a relatively high clinical dose (Table 8.3) and its use is associated with enzyme induction. For instance troglitazone lowers the plasma concentrations of known CYP3A4 substrates such as cyclosporine, terfenadine, atorvastatin, and ethinylestradiol. In contrast, the structurally related rosiglitazone (Figure 8.31) is administered at a lower dose and shows no evidence of enzyme induction. Concomitant administration of rosiglita-

O Fig. 8.31 Structures oftroglitazone (A) and rosiglitazone (B).

O Fig. 8.31 Structures oftroglitazone (A) and rosiglitazone (B).

zone (8 mg) did not effect the pharmacokinetics of the CYP3A4 substrates, nifedipine or ethinylestradiol. The clinical dose used closely relates to the receptor potency of these agents. For instance the EC50 values for troglitazone and rosiglitazone for affinity against the peroxisome proliferator-activated receptor y (PPAR-y) ligand binding domain, are 322 and 36 nM, respectively. Corresponding figures for elevation of P2 mRNA levels as a result of peroxisome proliferator-activated receptor y ag-onism are 690 and 80 nM, respectively. This increase in potency is even more marked in intact human adipocytes with affinities for PPAR-y of 1050 and 40 nM. Examination of these figures illustrates that troglitazone can be classed as a drug of weak affinity, similar to the Na+ channel blockers.

As a first rule for drug discovery/development programmes it seems prudent to obey the "Golden Rules" of drug design: "Ensure moderate daily dose size by having chosen a viable mechanism and then optimizing potency against the target whilst optimizing pharmacokinetics". This approach should result in a low dose as exemplified by the anti-diabetic compound troglitzone, a clinical CYP3A4 inducer which has a clinical dose of 200-600 mg and, rosiglitazone a more potent analogue requiring lower dose levels (2-12 mg), which is devoid of CYP3A4 induction in the clinic. This drive for a low dose also minimizes the chances of other potential toxicities


1 Ikeda K, Oshima T, Hidaka H, Takasaka T, Hearing Res. 1997, 107, 1-8.

2 Kenyon B, Browne F, D'Amato RJ, Exp. Eye Res. 1997, 64, 971-978.

3 Falik R, Flores BT, Shaw L, Gibson GA, Josephson ME, Marchlinski FE, Amer. J. Med. 1987, 82, 1102-1108.

4 Harris L, McKenna WJ, Rowland E, Holt DW, Storey GCA, Krikler DM, Circulation 1983, 67, 45-51.

5 Smith DA, Brown K, Neale MG, Drug Metab. Rev. 1985-86, 16, 365-388.

7 Hinson JA, Roberts DW, Ann. Rev. Pharmacol. Toxicol. 1992, 32, 471-510.

8 Cary RD, Binnie CD, Clin. Pharma-cokinet. 1996, 30, 403-415.

9 Riley RJ, Kitteringham NR, Park BK, Br. J. Clin. Pharmacol. 28, 482-487 (1989).

10 Bennett GD, Amore BM, Finnell RH, Wlodarczyk B, Kalhorn TF, Skiles GL, Nelson SD, Slattery JT, J. Pharmacol. Exp. Ther. 1996, 278, 1237-1242.

11 Tingle MD, Jewell H, Maggs JL, O'Neill PM, Park BK, Biochem. Pharmacol. 1995, 50, 1113-1119.

12 Miyamoto G, Zahid N, Uetrecht JP, Can. Chem. Res. Toxicol. 1997, 10, 414-419.

13 SpaldinV, Madden S, Pool WF, Woolf TF, Park BK, Br. J. Clin. Pharmacol. 1994, 38, 15-22.

14 Ju C, Uetrecht JP, Drug Metab. Dispos. 1998, 26, 676-680.

15 Stonier PD, Pharmacoepidemiol. Drug Safe. 1992, 1, 177-185.

16 Roden DM, In: The Pharmacological Basis for Therapeutics (Eds Goodman LS, Gillman A), pp. 839-874. McGraw-Hill, New York, 1995.

17 Chao Z, Liu C, Uetrecht JP, J. Pharmacol. Exp. Ther. 1995, 275, 1476-1483.

18 Maggs JL, Williams D, Pirmohamed M, Park BK, J. Pharmacol. Exp. Ther. 1995, 275, 1463-1475.

19 Uetrecht J, Zahid N, Tehim A, Fu JM, Rakhit S, Chemico-Biol. Interact. 1997, 104, 117-129.

20 Roberts P, Kitteringham NR, Park BK, J. Pharm. Pharmacol. 1993, 45, 663-665.

21 Cribb AE, Spielberg SP, Drug Metab. Dispos. 1990, 18, 784-787.

22 Coleman MD, Gen. Pharmacol. 1995, 26, 1461-1467.

23 Treiber A, Dansette PM, Amri HE, Girault JP, Giderow D, Mornon J-P, Mansy D, J. Amer. Chem. Soc. 1997, 119, 1565-1571.

24 Mansuy D, J. Hepatol. 1997, 26 (Suppl. 2), 22-25.

26 Desager JP, Clin. Pharmacokinet. 1994, 26, 347-355.

27 Liu ZC, Uetrecht JP, Drug Metab. Dispos. 2000, 28, 726-730.

28 Hepatic monitoring for tenidap in Scrip World Pharmaceutical News, 1995, 21, 2073.

29 Durant GJ, Emmett JC, Ganellin CR, Miles PD, Parsons ME, Prain HD, White GR, J. Med. Chem. 1977, 20, 901-906.

30 Smith DA, Johnson M, Wilkinson DJ, Xenobiotica 1985, 15, 437-444.

31 Nakadate M, Toxicol. Lett. 1998, 102-^103, 627-629.

32 Begnini R Guiliani A, In: Computer-Assisted Lead Finding and Optimization. (Eds Van de Waterbeemd H, Testa B, Folkers G), pp. 291-312. Wiley-VCH, Basel, 1997.

33 Begnini R, Richard AM, Methods Enzymol. 1998, 14, 264-276.

34 Barratt MD, Toxicol. Lett. 1998, 102-103, 617-621.

35 Richard AM, Toxicol. Lett. 1998, 102-103, 611-616.

36 Barratt MD, Cell Biol. Toxicol. 2000, 16, 1-13.

37 Hall AH, Toxicol. Lett. 1998, 102-103, 623-626.

38 Maran U, Karelson M, Katritzky AR, Quant. Struct. Activity Rel. 1999, 18, 3-10.

39 Vracko M, Novic M, Zupan J, Anal. Chim. Acta 1999, 384, 319-332.

40 Yang RSH, Thomas RS, Gustafson DL, Campain J, Benjamin SA, Verhaar HJM, Mumtaz MM, Environ. Health Perspect. 1998, 106 (Suppl.), 1385-1393.

41 Cronin MTD, Pharm. Pharmacol. Commun. 1998, 4, 157-163.

42 Olson H, Betton G, Stritar J, Robinsin D, Toxicol. Lett. 1998, 102-103, 535-538.

43 Sina JF, Ann. Rep. Med. Chem. 1998, 33, 283-291.

44 Todd MD, Ulrich RG, Curr. Opin. Drug Discov. Dev. 1999, 2, 58-68.

45 Nuwaysir EF, Bittner M, Barrett JC, Afshari CA, Mol. Carcinogen. 1999, 24, 153-159.

46 Kitteringham NR, Powell H, Clement YN, Dodd CC, Tettey JNA, Pirmo-hamed M, Smith DA, McLellan LI, Park BK, Hepatology 2000, 32, 321-333.

46 Burczynski ME, McMillian M, Ciervo J, Li L, Parker JB, Dunn RT, Hicken S, Farr S, Johnson MD, Toxicol. Sci. 2000, 58, 399-415.

47 Smith DA, Eur. J. Pharm. Sci. 2000, 11, 185-189.

Pharmacokinetics and Metabolism in Drug Design 123 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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