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Prediction of clearance
Using the scaling and correction factors described on previous pages, intrinsic hepatic clearance, liver blood flow and blood drug binding are combined in a model (well-stirred, parallel tube or dispersion) to predict net hepatic clearance. The value is combined with an estimate of renal clearance alone to predict net systemic clearance, or with renal clearance and ‘first-pass’ gut wall metabolism to predict net oral clearance (Howgate et al., 2006).
The in vitro data on enzyme kinetics required for input into Simcyp are the Vmax and Km values, or the intrinsic clearance values, for each enzyme involved in the metabolism of the compound of interest. More complex inputs reflecting allosteric effects at the active enzyme site can also be accommodated. Data from studies with cytosolic and S9 fractions can be used to account for non-CYP pathways in the liver, intestine or kidney, providing the facility to simulate metabolism by enzymes such as sulfotransferases, aldehyde oxidases, glutathione S-transferases, alcohol dehydrogenases or xanthine oxidases.
The Simcyp Simulator allows accurate prediction of in vivo drug clearance from in vitro data, not just for the average individual but across populations (Figure 5) (Howgate et al., 2006).
Figure 5. Predicted vs. observed clearance of drugs administered orally (left) or intravenously (right). The elipses represent the 90% confidence interval of the spread of both predicted and observed values in different individuals. The line is the line of identity.
Key: Apz = Alprazolam, Buf = Bufuralol, Caf = Caffeine, Chlr = Chlorzoxazone, Clz = Clozapine, Cyc = Cyclosporine, Dex = Dextromethorphan, Dic = Diclofenac, Met = Metoprolol, Mdz = Midazolam, Omp = Omeprazole, Phen = Phenacetin, S-mph = S-Mephenytoin, S-Wrf = S-Warfarin, Sld = Sildenafil, Sim = Simvastatin, Theo = Theophylline, Tlb = Tolbutamide, Tlt = Tolterodine, Trz = Triazolam, Zlp = Zolpidem
The Simcyp Simulator outputs a measure of variability as a result of the inclusion of data on:
- Proportional metabolism by each enzyme
- Genetic/environmental variations in enzyme abundance
- Ethnic differences in genotype frequencies and levels of CYP and UGT enzymes
- Physiological differences e.g. liver size and hepatic blood flow
- Changes in physiology and enzymology with age
