Pharmacokinetic-based toxic effects

Two distinct bases for these types of effects may be distinguished pharmacokinetic and pharmacodynamic. Pharmacokinetic-based toxic effects are due to an increase in the concentration of the compound or active metabolite at the target site. This may be due to an increase in the dose, altered metabolism or saturation of elimination processes for example. An example is the increased hypotensive effect of debrisoquine in poor metabolizers where there is a genetic basis for a reduction in metabolic clearance of the drug (see Chapter 5). 

TDM can detect interindividual variability in pharmacokinetics that can determine clinical outcome (83, 84, 85, 86, 87, 88 and 89). It is essentially a refinement of the traditional approach of adjusting dose based on clinical response. Using this strategy, the clinician titrates the dose based on an assessment of efficacy versus the development of nuisance or toxic effects. The discussion in this chapter has enumerated those pharmacokinetic factors that may produce variable clinical outcomes in different patients taking the same medication. TDM can be used to detect those differences among patients to guide rational dose adjustment. 

The N-oxide of indicine (49) exhibits anti-tumour activity in experimental tumour systems, without some of the toxic effects associated with other pyrrolizidine alkaloids. The N-oxides of echinatine and europine show similar anti-tumour activity against P 388 lymphocytic leukaemia tumours.23 Indicine N-oxide is metabolized to the free base in rabbits and humans,62 although the N-oxide is the more active anti-tumour agent. It has been suggested that the conversion of indicine N-oxide into indicine is not essential for its anti-tumour activity.63 Indicine N-oxide is the first pyrrolizidine alkaloid to be tested as an anti-tumour agent in humans. The toxicity and pharmacokinetics of this compound have been studied in 29 patients with advanced cancers.64 The major toxic effect was myelosuppression, but acute liver damage was not observed. 

Dose selection for subchronic and chronic toxicology studies should be based on the results from acute toxicity studies and pharmacokinetic evaluations. The three typical dose levels are (a) a no-toxic-effect level, which should be at least equivalent to, and hopefully a multiple of, the proposed human dose, (b) a dose level that produces a toxic effect in clinical observations, clinical pathology, or histopathologic changes, and (c) a dose level between these two. 

The pharmacokinetics of raltitrexed, and hence its toxic effects, particularly on the bone marrow and gut, are directly related to creatinine clearance (8). It is recommended that the dose be reduced and dosage interval increased in patients with mild to moderate renal impairment, based on the fact that raltitrexed is mainly excreted unchanged in the urine. 

Dtxetaxel is indicated for breast cancer after failure of prior chemotherapy and for non-small lung carcinoma after failure of platinum-based therapy. Toxic effects include neutropenia. Ouid retention, mutagenesis, rash, and neurological symptoms." Peripheral blood counts should be performed because of myclosupprcssion. Pharmacokinetics indicate a three-compartment model with half-lives of 4 and 36 minutes and I l.l hours. The drug is 94% protein bound. 

A lower incidence of myelosuppression has been observed and reported during studies on Abraxane but other toxic effects (sensory neuropathy, mucositis) are similar to those seen with Taxol given at high doses. Abraxane has been reported to produce keratopathy, which is a toxic effect rarely seen with drugs. Thus, as with the liposomal formulations described earlier (Section VIII.A.), the administration of nanoparticle based formnlations can dramatically alter the pharmacokinetics, the distribution of the drug in both tissnes and tumors, and the toxicity profile. Also, similar to what has been found with liposomes, the mechanism(s) by which nanoparticles release their drug payload is not well nnderstood as yet. 

Theophylline is not only characterized by a narrow therapeutic index and distinct relationships between serum concentration and therapeutic and toxic effects, but also by a high interindividual pharmacokinetic variabihty. This variability is predominantly based on a high patient-to-patient variability in the metabolic clearance of theophylline that is confounded by numerous additional physiological, pathophysiological, and enviromnental factors. Intravenous theophylhne (given as aminophyl-line), for example, has been shown to result in considerable variations in serum concentrations among patients despite the same dose, and theophylline dose requirements to maintain serum concentration in the range of 10 to 20 lig/ml varied from 400 to 3200 mg/day. ... 

BDE transformation products, such as hydroxylated BDEs, offer similar analytical challenges to BDEs. Certain hydroxylated BDEs exhibit structural similarities to th)moxine and estrogen and may produce toxic effects [104,105]. LC approaches are typically preferred over GC approaches, since derivitization steps are not required. Lupton et al. [106], and Kato et al. [107] each developed LC—MS/MS methods for determination of OH-BDEs, based on APCI or ESI operated in the negative-ion mode. Lai et al. [108] employed UHPLC with ESI—MS/MS to separate nine OH-BDEs in under 7 min (see Figure 13.7). The method was validated using spiked rat plasma samples and applied to a pharmacokinetic study of 6-OH-BDE-47 in rats dosed with this compoimd. Chang et al. [109] also... 

While carboplatin has the same mechanism of action as cisplatin, it has a much less toxic side-effect profile than cisplatin. The pharmacokinetics of carboplatin are best described by a two-compartment model, with an a half-life of 90 minutes and a terminal half-life of 180 minutes. Carboplatin is eliminated almost entirely by the kidney by glomerular filtration and tubular secretion. Many chemotherapy regimens dose carboplatin based on an area under the curve (AUC), which is referred to... 

Absorption, Distribution, Metabolism, and Excretion. There are no data available on the absorption, distribution, metabolism, or excretion of diisopropyl methylphosphonate in humans. Limited animal data suggest that diisopropyl methylphosphonate is absorbed following oral and dermal exposure. Fat tissues do not appear to concentrate diisopropyl methylphosphonate or its metabolites to any significant extent. Nearly complete metabolism of diisopropyl methylphosphonate can be inferred based on the identification and quantification of its urinary metabolites however, at high doses the metabolism of diisopropyl methylphosphonate appears to be saturated. Animal studies have indicated that the urine is the principal excretory route for removal of diisopropyl methylphosphonate after oral and dermal administration. Because in most of the animal toxicity studies administration of diisopropyl methylphosphonate is in food, a pharmacokinetic study with the compound in food would be especially useful. It could help determine if the metabolism of diisopropyl methylphosphonate becomes saturated when given in the diet and if the levels of saturation are similar to those that result in significant adverse effects. 

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