1. (a) Before; (b) after; (c) after; (d) after; (e) before; (f ) after.

2. (a) Yes; (b) yes; (c) no (MW > 600).

3. If computer programs could estimate log(P) values on the basis of chemical structure, then the required laboratory time for drug development could be shortened. The determination of the relative solubilities of pharmaceutical candidates by allowing each compound to equilibrate between water and an organic phase would no longer be necessary.

4. Perhaps N-acetylcysteine would conjugate to some of the N-acetyl-p-benzoquinone imine that is produced by the metabolism of acetaminophen, thereby preventing the depletion of the liver’s supply of glutathione.

5. In Phase I clinical trials, approximately 10 to 100 usually healthy volunteers are typically enrolled in a study designed to assess safety. In contrast, a larger number of subjects are enrolled in a typical Phase II trial. Moreover, these persons may benefit from the drug administered. In a Phase II trial, efficacy, dosage, and safety can be assessed.

6. The binding of other drugs to albumin could cause extra coumadin to be released. (Albumin is a general carrier for hydrophobic molecules.)

7. A drug that inhibits a P450 enzyme may dramatically affect the disposition of another drug that is metabolized by that same enzyme. If this inhibited metabolism is not accounted for when dosing, the second drug may reach very high, and sometimes toxic, levels in the blood.

8. Unlike competitive inhibition, noncompetitive inhibition cannot be overcome with additional substrate. Hence, a drug that acts by a noncompetitive mechanism will be unaffected by changing levels of the physiological substrate.

9. An inhibitor of MDR could prevent the efflux of a chemotherapeutic drug from tumor cells. Hence, this type of an inhibitor could be useful in averting resistance to cancer chemotherapy.

10. Agents that inhibit one or more enzymes of the glycolytic pathway could act to deprive trypanosomes of energy and thus be useful for treating sleeping sickness. A difficulty is that glycolysis in the host cells also would be inhibited.

11. Imatinib is an inhibitor of the Bcr-Abl kinase, a mutant kinase present only in tumor cells that have undergone a translocation between chromosomes 9 and 22 (Figure 14.34). Before initiating treatment with imatinib, we could sequence the DNA of the tumor cells and determine (a) whether this translocation has taken place and (b) whether the sequence of bcr-abl carries any mutations that would render the kinase resistant to imatinib. If the translocation has not taken place or if the gene carries resistance mutations, then imatinib would likely not be an effective treatment for the patient carrying this particular tumor.

A48

12. Sildenafil increases cGMP levels by inhibiting the phosphodiesterase-mediated breakdown of cGMP to GMP. Intracellular cGMP levels can also be increased by activating its synthesis. This activation can be achieved with the use of NO donors (such as sodium nitroprusside and nitroglycerin) or compounds that activate guanylate cyclase activity. Drugs that act by the latter mechanism are currently in clinical trials.

13. A reasonable mechanism would be an oxidative deamination following an overall mechanism similar to that in Figure 36.10, with release of ammonia.

14. K_I ≈ 0.3 nM. IC₅₀ ≈ 2.0 nM. Yes, compound A should be effective when taken orally because 400 nM is much greater than the estimated values of K_I and IC₅₀.