**4. Drug metabolism and drug design**

The knowledge of drug metabolism is important in new drug design and development. If the new drug is quickly metabolised in the body, some non-reactive groups are added which resist the drug metabolism. For example, tolbutamide (**Figure 18**) is an anti-diabetic drug and it has a shorter half-life (2.5 hrs). It undergoes the process of metabolism and the methyl group converted into a carboxyl group. If the methyl group is replaced by the chlorine atom, then this compound (chlorpropamide) achieves a longer half-life (12–15 hrs) as compared to tolbutamide [21]. Drug metabolism has a significant effect on pharmacokinetic, pharmacodynamic and safety of a drug [22]. Some drugs are administered in inactive forms and are called as prodrugs. In prodrug, a drug is chemically modified to overcome its problems of absorption,

*Drug Metabolism: Phase I and Phase II Metabolic Pathways DOI: http://dx.doi.org/10.5772/intechopen.112854*

**Figure 18.** *Drug metabolism and drug design.*

route of administration, metabolism and excretion. Prodrugs have labile functional groups which are easily metabolised in the body. For example, ester, phosphate, carbamate. Masking of polar functional improves oral bioavailability [23]. For example, chloramphenicol palmitate and bacampicillin are prodrugs of chloramphenicol and ampicillin respectively.

### **5.** *In silico* **pharmacokinetic studies**

About 40% of new drugs fail in clinical trials because of poor pharmacokinetic properties. Nowadays pharmacokinetic properties of new compounds are evaluated by swissADME, ADMETlab and pkCSM web tools. 3D structure of compounds are generated on online software and pharmacokinetic properties ADMET (absorption, distribution, metabolism, excretion and toxicity) are computed. The GI absorption, BBB permeation, P-gp substrate, cytochrome P450 enzyme inhibition/induction, skin permeation are critical for the oral activity of drug molecules and these properties can be predicted. The prediction of pharmacokinetic properties helps to understand the behaviour of drug molecules in the human body. *In silico* predictions help to reduce the costly experimental approach [24]. The drug likeness of new molecules is also predicted by Lipinski rule of five [25]. According to this rule, drug molecules having more than five hydrogen bond donors, more than 10 hydrogen bond acceptor, logP more than five and molecular weight more 500 dalton are less likely to be orally active. High lipophilicity leads to the poor absorption of drug molecules. Similarly, compounds having big weights are less likely to absorb from GIT. About 80% drugs have molecular weight less than 450. The molecules having polar surface area less than 140°A and number of rotatable bond less than 10 also show good oral bioavailability. Drug molecules that follow the RO5 have increased chances of reaching the market and have less probability to fail during the clinical trials [26].
