Pharmacokinetics and 11 related topics 11.1 The three phases of drug may be absorbed through the mucosal membranes of the mouth, but most passes down into the stomach where action it encounters gastric juices and hydrochloric acid. Th ese chemicals aid in the digestion of food and will treat a Th ere are three phases involved in drug action. Th e drug in a similar fashion if it is susceptible to breakdown fi rst of these is the pharmaceutical phase . For an orally and is not protected within an acid-resistant pill or cap- administered drug, this includes the disintegration of a sule. For example, the fi rst clinically useful penicillin was pill or capsule in the gastrointestinal tract (GIT), the broken down in the stomach and had to be administered release of the drug, and its dissolution. Th e pharmaceu- by injection. Other acid-labile drugs include the local tical phase is followed by the pharmacokinetic phase , anaesthetics and insulin . If the drug does survive the which includes absorption from the GIT into the blood stomach, it enters the upper intestine where it encoun- supply, and the various factors that aff ect a drug’s survival ters digestive enzymes that serve to break down food. and progress as it travels to its molecular target. Th e fi nal Assuming the drug survives this attack, it then has to pharmacodynamic phase involves the mechanism by pass through the cells lining the gut wall. Th is means that which a drug interacts with its molecular target and the it has to pass through a cell membrane on two occasions: resulting pharmacological eff ect. fi rst to enter the cell and then to exit it on the other side. In previous chapters, we have focused on drug tar- Once the drug has passed through the cells of the gut gets and drug design, where the emphasis is on the wall, it can enter the blood supply relatively easily, as the pharmaco dynamic aspects of drug action, for example cells lining the blood vessels are loose fi tting and there optimizing the binding interactions of a drug with its tar- are pores through which most drugs can pass. In other get. However, the compound with the best binding inter- words, drugs enter blood vessels by passing between actions for a target is not necessarily the best drug to use cells, rather than through them. in medicine. Th is is because a drug has to reach its target Th e drug is now transported in the blood to the body’s in the fi rst place if it is to be eff ective. Th erefore, when ‘customs offi ce’—the liver. Th e liver contains enzymes that carrying out a drug design programme, it is important to are ready and waiting to intercept foreign chemicals, and study pharmacokinetics alongside pharmacodynamics. modify them such that they are more easily excreted—a Th e four main topics to consider in pharmacokinetics process called drug metabolism (section 11.5). Following are: absorption, distribution, metabolism, and excretion this, the drug has to be carried by the blood supply around (oft en abbreviated to ADME). the body to reach its eventual target, which may require crossing further cell membranes—always assuming that 11.2 it is neither excreted before it gets there nor diverted to A typical journey for an parts of the body where it is not needed. orally active drug It can be seen that stringent demands are made on any orally administered drug. It must be stable to both Th e preferred method of drug administration is the oral chemical and enzymatic attack. It must also have the cor- route, and so we shall consider some of the hurdles and rect physicochemical properties to allow it to reach its hazards faced by such a drug in order to reach its even- target in therapeutic concentrations. Th is includes effi - tual target. When a drug is swallowed, it enters the GIT, cient absorption, eff ective distribution to target tissues, which comprises the mouth, throat, stomach, and the and an acceptable rate of excretion. We will now look upper and lower intestines. A certain amount of the drug more closely at the various stages. Patrick97397.indb 153 11/28/2012 9:14:13 PM 154 Chapter 11 Pharmacokinetics and related topics Ionized amine Non-ionized amine 11.3 Drug absorption (free base) H In order to be absorbed effi ciently from the GIT, a drug N H N H + H must have the correct balance of water versus fat solubil- ity. On one hand, if the drug is too polar (hydrophilic), it Receptor interaction Crosses will fail to pass through the fatty cell membranes of the and water solubility membranes gut wall (section 1.2.1). On the other hand, if the drug is FIGURE 11.1 Equilibrium between the ionized and non- too fatty (hydrophobic), it will be poorly soluble in the ionized form of an amine. gut and will dissolve in fat globules. Th is means that there will be poor surface contact with the gut wall, resulting in poor absorption. Note that when the concentrations of the ionized It is noticeable how many drugs contain an amine and unionized amines are identical (i.e. when = + + functional group. Th ere are good reasons for this. [RNH2 ] [RNH3 ]), the ratio ([RNH 2 ]/[RNH3 ]) is 1. Amines are oft en involved in a drug’s binding interac- As log 1 = 0, the Henderson–Hasselbalch equation will = tions with its target. However, they are also an answer simplify to pH p Ka . In other words, when the amine is = to the problem of balancing the dual requirements of 50% ionized, pH p Ka . Th erefore, drugs with a pK a of water and fat solubility. Amines are weak bases and it 6–8 are approximately 50% ionized at blood pH (7.4) or is found that many of the most eff ective drugs contain the slightly acidic pH of the intestines. amine groups having a p K a value in the range 6–8. In Th e hydrophilic/hydrophobic character of the drug other words, they are partially ionized at the slightly is the crucial factor aff ecting absorption through the acidic and alkaline pHs present in the intestine and gut wall; in theory, the molecular weight of the drug blood, respectively, and can easily equilibrate between should be irrelevant. For example, ciclosporin is suc- their ionized and non-ionized forms. Th is allows them cessfully absorbed through cell membranes although it to cross cell membranes in the non-ionized form, while has a molecular weight of about 1200. In practice, how- the presence of the ionized form gives the drug good ever, larger molecules tend to be poorly absorbed. As a water solubility and permits good binding interactions rule of thumb, orally absorbed drugs tend to obey what with its target binding site ( Fig. 11.1 ). is known as Lipinski’s rule of fi ve . Th e rule of fi ve was Th e extent of ionization at a particular pH can be derived from an analysis of compounds from the World determined by the Henderson–Hasselbalch equation : Drugs Index database aimed at identifying features that were important in making a drug orally active. It was found that the factors concerned involved numbers that []RNH pH=+ pK log 2 are multiples of fi ve: a []RNH+ 3 • a molecular weight less than 500; • no more than 5 hydrogen bond donor (HBD) groups; where [RNH2 ] is the concentration of the free base and + [RNH3 ] is the concentration of the ionized amine. Ka is • no more than 10 hydrogen bond acceptor groups; the equilibrium constant for the equilibrium shown in • a calculated log P value less than +5 (log P is a measure Fig. 11.1 and the Henderson–Hasselbalch equation can of a drug’s hydrophobicity—section 14.1). be derived from the equilibrium constant: Th e rule of fi ve has been an extremely useful rule of [][]HRNH+ thumb for many years, but it is neither quantitative nor = 2 Ka + foolproof. For example, orally active drugs, such as ator- []RNH3 + vastatin , rosuvastatin , ciclosporin , and vinorelbine , do [][]HRNH =− 2 Therefore pKa log + not obey the rule of fi ve. It has also been demonstrated []RNH3 that a high molecular weight does not in itself cause poor + []RNH = −− 2 oral bioavailability. One of the reasons that the molecular log[H ] log + []RNH3 weight appears to be important is that larger molecules []RNH invariably have too many functional groups capable of =−pH log 2 []RNH+ forming hydrogen bonds. Another source of debate con- 3 cerns the calculation of the number of hydrogen bond []RNH Therefore pHHp=+K log 2 acceptors (HBAs). In Lipinski’s original paper, the num- a []RNH+ 3 ber of HBAs corresponded to the total number of oxygen Patrick97397.indb 154 11/28/2012 9:14:14 PM Drug absorption 155 and nitrogen atoms present in a structure. Th is was done provides information on MWt, log P, HBDs, HBAs, for simplicity’s sake, but most medicinal chemists would rotatable bonds, and polar surface area for drugs cov- discount weak HBAs, such as amide nitrogens (see also ered in this text. section 1.3.2 and Appendix 7). Th erefore, it is better to Polar drugs that break the above rules are usu- view Lipinski’s rules as a set of guidelines rather than rules. ally poorly absorbed and have to be administered by Lipinski himself stated that a compound was likely to be injection. Nevertheless, some highly polar drugs are orally active as long as it did not break more than one of absorbed from the digestive system as they are able to his ‘rules’.