Drugs interactions based

Kanamitsu SI, Ito K, Okuda H, et al. Prediction of in vivo drug-drug interactions based on mechanism-based inhibition from in vitro data inhibition of 5-fluorouracil metabolism by (E)-5-(2-bromovinyl)uracil. Drug Metab Dispos 2000 28(4) 467 t74. 

Appendix Drug interactions based on physical mechanisms... 

In the past year, several reports on the subject of herb-drug interactions have been published. These range from collations of individual case reports, to predictions of herb-drug interactions based on the hypothesized mechanisms of action of the herbs, to clinical trials in healthy individuals, to reviews of all of the above. 

While drug interactions based on pharmacokinetics do occur with sedative-hypnotics, the most common drug interaction is additive CNS depression. Additive effects can be predicted with concomitant use of alcoholic beverages, anticonvulsants, opioid analgesics and phenothiazines. Less obvious but equally important is enhanced CNS depression with many antihistamines, antihypertensives, and antidepressants of the tricyclic class. The answer is (A). 

Quinine is metaboiized in the liver to the 2 -hydroxy derivative, followed by additional hydroxylation on the quinuciidine ring, with the 2,2 -dihydroxy derivative as the major metabolite. This metabolite has low activity and is rapidly excreted. The metabolizing enzyme of quinine is CYP3A4. With the increased use of quinine and its use in combination with other drugs, the potential for drug interactions based on the many known substrates for CYP3A4 (see Chapter 10) is of concern (36). 

Fahmi OA, Maurer TS, Kish M, Cardenas E, Boldt S and Nettleton D (2008) A combined model for predicting CYP3A4 clinical net drug-drug interaction based on CYP3A4 inhibition, inactivation, and induction determined in vitro (Drug Metab Dispos (2008) 36 (1698-1708). Drug Metabolism and Disposition 36(9) 1975. 

Following concurrent administration of two drugs, especially when they are metabolized by the same enzyme in the liver or small intestine, the metabolism of one or both drugs can be inhibited, which may lead to elevated plasma concentrations of the dtug(s), and increased pharmacological effects. The types of enzyme inhibition include reversible inhibition, such as competitive or non-competitive inhibition, and irreversible inhibition, such as mechanism-based inhibition. The clinically important examples of drug interactions involving the inhibition of metabolic enzymes are listed in Table 1 [1,4]. 

Before an antiviral agent becomes a drug, advanced toxicity testing, pharmacological combination, and drug-interaction studies are needed. The use of new cell-based assays that can predict mitochondrial toxicity, lactic acidosis, peripheral neuropathy, anemia, hypersensitivity, lipodystrophy, and other potential side effects can alleviate these issues (Stuyver et al. 2002). 

L. G. Reevaluating equilibrium and kinetic binding parameters for lipophilic drugs based on a structural model for drug interaction with biological membranes. 

Interview the patient to assess complementary or alternative medication use. Counsel appropriately based on indications and drug interactions. 

Institute appropriate pharmacotherapy based on lipid abnormality. Obtain appropriate baseline labs to monitor for adverse drug effects. Assess potential disease and drug interactions that may affect choice or intensity of pharmacotherapy. 

Develop a treatment plan with the patient and other health care professionals if appropriate. Choose therapeutic options based on the underlying cause of nausea and vomiting, duration and severity of symptoms, comor-bid conditions, medication allergies, presence of contraindications, risk of drug-drug interactions, and treatment adverse-effect profiles. 

Adjust drug dosages based on the patient s creatinine clearance or evidence of adverse drug reactions or interactions. 

SSRIs are the drugs of choice for PD. All SSRIs have demonstrated effectiveness in controlled trials, with 60% to 80% of patients achieving a panic-free state.28,48,49 With similar efficacy reported and no trials comparing SSRIs with other SSRIs, selection generally is based on pharmacokinetics, drug interactions, side effects, and cost differences (see Chap. 35 for more discussion). The most common side effects of SSRIs include headaches, irritability, nausea and other gastrointestinal complaints, insomnia, sexual dysfunction, increased anxiety, drowsiness, and tremor.49 SSRIs should not be discontinued abruptly to avoid a withdrawal syndrome characterized by dysphoric mood, irritability, and agitation. 

Mason, R. R Rhodes, D. G. Herbette, L. G., Reevaluating equilibrium and kinetic binding parameters for lipophilic drugs based on a structural model for drug interaction with bilogical membranes, J. Med. Chem. 34, 869-877 (1991). 

Jones, B. C., Ciark, S. E., Human cytochromes P450 and their role in metabolism based drug-drug interactions, in Drug-Drug Interactions. Rodrigues, A. D. (ed.), 2001, Chapter 3, 55-88. Marcel Dekker Inc. New York. 

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