Pharmacokinetic interactions bioavailability

In its original formulation as a hard gel capsule (saquinavir-H Invirase), oral saquinavir was poorly bioavailable (about 4% in the fed state). It was therefore largely replaced in clinical use by a soft gel capsule formulation (saquinavir-S Fortovase), in which absorption was increased approximately threefold. However, reformulation of saquinavir-H for once-daily dosing in combination with low-dose ritonavir (see Ritonavir) has both improved antiviral efficacy and decreased the gastrointestinal side effects typically associated with saquinavir-S. Moreover, coadministration of saquinavir-H with ritonavir results in blood levels of saquinavir similar to those associated with saquinavir-S, thus capitalizing on the pharmacokinetic interaction of the two agents. 

The design of an exploratory food interaction bioavailability study with drug XYZ1234 is presented below. In this given project, the food interaction study was initiated parallel to a hADME study just after completion of the first-in-man study. In this study, the collection, handling, and interpretation of pharmacokinetic data were in the main focus. 

Propranolol 80 mg three times daily did not affect the pharmacokinetics of a single 20-mg dose of quinapril in 10 healthy subjects. The pharmacokinetics of ramipril 5 mg daily were unaffected by propranolol 40 mg twice daily. Similarly, the manufacturer of fosinopril reports that the bioavailability of fosinoprilat, its active metabolite, was not altered by propranolol. Another study found no significant pharmacokinetic interaction between cilazapril 2.5 mg daily and propranolol 120 mg daily in healthy subjects, but the reductions in blood pressure were about doubled and long-lasting in healthy subjects and in patients with hyperten-... 

No evidence of either a pharmacokinetic or adverse pharmacodynamic interaction was seen in 12 healthy subjects given single doses of nifedipine retard 20 mg and lisinopril 20 mg the effects on blood pressttre were additive. Similarly, there was no pharmacokinetic interaction between single doses of slow-release nifedipine 20 mg and benazepril 10 mg in healthy subjects the effects on blood pressure were additive and the tach-ycardic effect of nifedipine was attenuated by benazepril. The manufacturer of fosinopril notes that the bioavailability of fosinoprilat, the active metabolite, was not altered by nifedipine. - Similarly, the manufacturer of moexipril notes that no clinically important pharmacokinetic interaction occurred with nifedipine in healthy subjects. ... 

Symptomatic hypotension may occur when an angiotensin II receptor antagonist is started in patients taking high-dose diuretics. Potassium levels may be either increased, decreased or not affected. No clinically relevant pharmacokinetic interactions appear to occur between candesartan, eprosartan, irbesartan, losartan, telmisartan or valsartan and hydrochlorothiazide, although the bioavailability of hydrochlorothiazide may be modestly reduced. Similarly, there is no clinically significant pharmacokinetic interaction between valsartan and furosemide. 

Furosemide. In 12 healthy subjects the relative bioavailability of furosemide 40 mg was reduced by about 26% when it was given with valsartan 160 mg. However, this pharmacokinetic interaction had no influence on the diuretic effect of furosemide. Simultaneous use of valsartan and furosemide did not modify the pharmacokinetics of valsartan. ... 

The concurrent use of a lifamycin and isoniazid is common and therapeutically valuable, but there is evidence that the incidence of hepatotoxicity may be increased, particularly in slow acetylators of isoniazid. One study su ests the bioavailability of rifampicin may be reduced by isoniazid but other studies found no pharmacokinetic interaction. Rifabutin and rifampicin do not alter the pharmacokinetics of isoniazid. 

In general there appears to be no pharmacokinetic interaction between digoxin and beta biockers, although talinolol and carvedilol appear to increase the bioavailability of digoxin. Pharmacodynamic interactions, resulting in additive bradycardia, are possible. A few cases of excessive bradycardia have been reported when propranolol was used to control digitalis-induced arrh i h-mias. 

Both pharmacodynamic and pharmacokinetic interactions may have positive effects, such as increasing the efficacy or bioavailability of drugs or botanicals. Such positive therapeutic interactions are not covered in this text, unless the interaction also poses a safety concern. 

Drug interactions are a serious problem, and pharmacokinetic interactions have several molecular bases. One is enzyme induction, which usually results in decreased bioavailability. The decreased bioavailabihty of a dmg can be the result of induction by that same dmg or by another dmg. A classic example is the decreased... 

These results confirm the hypothesis that the immunological activity of a polysaccharide is dependent on a specific conformational feature and the presence of a certain number of anionic domains. In our opinion, the approach to a rational drug design has to include the production of radio-, fluorescence- or gold-labeled polysaccharides and antibodies. These tools will help to explain the requirements for an optimal polysaccharide-immune cell interaction. This technique could also be useful for localizing the site of binding on the surface of the immune cell thus giving information on the pharmacokinetic and bioavailability of polysaccharides after oral and parenteral application. 

The Committee for Proprietary Medicinal Products [8] applied the BCS, with certain requirements, to dispense with bioequivalency tests if the active pharmaceutical ingredient is class I and the in vitro dissolution of the finished dosage form is fast [9], An active substance is considered highly soluble if the amount contained in the HDS of an IR product is dissolved in 250 ml of each of three buffers within the range of pH 1-8 at 37°C (e.g., pH 1.0, 4.6, and 6.8). There should be linear and complete absorption, which indicates HP to reduce the possibility of an IR dosage form influencing the bioavailability [8], The similarity of the dissolution profiles of the test and reference products is demonstrated in each of three buffers within the range of pH 1-8 at 37°C (e.g., pH 1.0,4.6, and 6.8). If there is rapid dissolution of the product, where at least 85% of the active substance is dissolved within 15 min, no further comparison of the test and reference is required. Further requirements include that excipients be well established and have no interaction with the pharmacokinetics of the active substance and that the method of manufacture of finished product... 

The inhibitor has excellent pharmacokinetics in both mice and rats, with high bioavailabilities (82 and 74%, respectively) [113]. Additionally, the potential for drug-drug interactions after administration of ARRY-142886 is low as it does not inhibit any of the major cytochrome p450 isoforms below 20 xM. 

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