Design of drugs through a consideration of drug metabolism and pharmacokinetics

Abstract

Drug metabolism input to the discovery process has been to date largely on an empirical case by case basis. Considerable advances have been made, such that basic rules can be applied to the behaviour of a compound in man based on physico-chemistry and structure. This is particularly true in the area of the cytochrome P-450 enzymes, the principal enzymes involved in the primary clearance of drugs. The major human forms, CYP2D6, CYP2C9 and CYP3A4 all have distinct substrate preferences which are being catalogued and rationalised. Such understandings will not only impact on existing drugs. Since the enzymes and systems will remain the same, these understandings can be applied to the design of molecules for the targets of the future, whilst the structure activity relationships of those targets are being researched and revealed.

Predicting Drug Disposition via Application of BCS: Transport/Absorption/ Elimination Interplay and Development of a Biopharmaceutics Drug Disposition Classification System

“…The seven identified drugs plus mannitol in their data set included Class 1 high extraction ratio drugs (metoprolol, propranolol, and verapamil), which of course would be expected to show low bioavailability; BDDCS Class 2 intermediate to low extraction ratio compounds (indomethacin, carbamazepine and warfarin), which would be expected to show intermediate to high bioavailability; timolol (probably BDDCS Class 2), a compound with higher clearance than the other Class 2 compounds, but less than the Class 1 compounds, and therefore expected to have intermediate bioavailability among these 7 drugs; and finally only one unmetabolized substance, mannitol (probably BDDCS Class 3), with very poor permeability, that would be expected to show poor bioavailability. So in essence, this report (53) just confirms the finding of Smith (19) that more permeable lipophilic compounds make good substrates for CYP enzymes, as the fraction not metabolized in 30 min of incubation is a measure of clearance, but the method will not be able to account for differences in bioavailability for Class 2 compounds that result from transporter-enzyme interplay, or for Class 3 drugs where uptake transporters will be the defining determinant of bioavailability. As outlined here, incorporation of recent scientific understanding should allow the pharmaceutical sciences community to develop a DPR parameter with predictability [i.e., it is not true that permeability of 80% of all compounds is due to passive diffusion; hepatocytes (or some other system that maintains the architecture of transporters and enzymes) should be used for the metabolism studies, not microsomes or the S9 fraction, so to include transporter-enzyme interplay; the fraction of total clearance that is attributable to metabolism rather than the metabolic clearance is the "permeability" parameter that differentiates BDDCS classes; both influx and efflux transporters must be considered; although clearance is a reasonable predictor of bioavailability for Class 1 compounds, this will often not be true for drugs from Classes 2, 3 and 4 where transporters cause differential effects between a Solubility classification was predominantly gathered from the literature (1,(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18).…”

“…2). We are unaware that this simple categorization under BCS has previously recognized the correlation and fact that the high permeability of the Classes 1 and 2 compounds allows ready access to the metabolizing enzymes within hepatocytes, although Smith (19) has noted that more permeable lipophilic compounds make good substrates for cytochrome P450 (CYP) enzymes. Note that the differential permeability characteristics defined under BCS do not necessarily reflect differences in permeability into hepatocytes, as a number of Class 3 and Class 4 compounds are eliminated into the bile.…”

In Vitro Studies on the Oxidative Metabolism of 20(S)-Ginsenoside Rh2 in Human, Monkey, Dog, Rat, and Mouse Liver Microsomes, and Human Liver S9

“…The permeability criterion used is responsible for the discrepancy because Rh2 was found to have a high intrinsic permeability (P a-b value up to 3 ϫ 10 Ϫ6 cm/s) versus the apparent low permeability due to efflux by P-gp (Yang et al, 2011). As a highly permeable lipophilic compound (cLog P ϭ 4.0), Rh2 is very likely a good substrate for P450 enzymes (Smith, 1994). This finding is consistent with the results from the animal experiments.…”

Optimization of metabolic stability as a goal of modern drug design

“…Substrates are lipophilic molecules, either neutral or basic, with site of oxidation often a basic nitrogen (N-dealkylation) or allylic carbon. 5 Compounds bound to the active site of P4503A are not constrained to the same de®ned substrate structure±activity relationship as with CYP2D6, accounting for its much broader substrate speci®city. 6…”