Pharmacokinetic profile bioavailability

The separation of enantiomers is a very important topic to the pharmaceutical industry. It is well recognized that the biological activities and bioavailabilities of enantiomers often differ [1]. To further complicate matters, the pharmacokinetic profile of the racemate is often not just the sum of the profiles of the individual enantiomers. In many cases, one enantiomer has the desired pharmacological activity, whereas the other enantiomer may be responsible for undesirable side-effects. What often gets lost however is the fact that, in some cases, one enantiomer may be inert and, in many cases, both enantiomers may have therapeutic value, though not for the same disease state. It is also possible for one enantiomer to mediate the harmful effects of the other enantiomer. For instance, in the case of indacrinone, one enantiomer is a diuretic but causes uric acid retention, whereas the other enantiomer causes uric acid elimination. Thus, administration of a mixture of enantiomers, although not necessarily racemic, may have therapeutic value. 

Unity resulted in 4234 hits. After application of several filters and clustering of the remaining 1975 molecules, compounds from 18 of the 27 clusters were screened in Xenopus oocytes. One compound with an IC50 of 5.6pM belonged to a new class of Kvl.5 blockers and exhibited a favorable pharmacokinetic profile. After further optimization, compound 73 (IC50 = 0.7pM Fig. 16.9) resulted, with good oral bioavailability in rats [145]. 

Compound (1) suffered from an unfavorable pharmacokinetic profile when studied in rats. It is cleared very rapidly from rat plasma (half-life, t 2 — 0.4/z) and is poorly bioavailable F — 2%), as reflected by the low plasma concentration (area under the plasma concentration-time curve, AUCo oo = 0.2pMh) following a single oral dose of 25mg/kg in rats [42]. The main challenge was to further optimize this series to obtain NS3 protease inhibitors with low-nanomolar cell-based potency (EC5q< 10 nM) and with an adequate pharmacokinetic profile for oral absorption. 

The pharmacokinetic profile of (16) and its two analogues were investigated in Sprague-Dawley rats. Removal of the metabolically labile tert-butyl group on the aryl moiety slowed metabolism and the rate of clearance. However, the overall half-life of (17a) was unaffected because of a lower volume of distribution. On the other hand, (17b) showed an increased half-life (ca. 3h versus 1 h) compared to (16) and (17a). While the oral bioavailability of (16) was negligible, (17a) and (17b) were better absorbed, with bioavailability values of 39% and 17%, respectively. While undoubtedly improved in terms of pharmacokinetics compared to (16), the bioactivity of (17a) and (17b) awaits validation in vivo. 

Pharmacokinetic profile Pharmacodynamic profile Bioequivalence and bioavailability Acute toxicity Chronic toxicity... 

The physical properties of an API can significantly effect the physical and chemical stability of a formulation, its bioavailability and ultimately they can modify the pharmacokinetic profile of the drug. This issue will be discussed in more detail in section 3.4. For these reasons it is necessary to control the physical form of the API at the Pures crystallization step, and throughout the subsequent formulation steps, to ensure a consistent delivery profile to the patient. This control strategy must be documented in the New Drug Application... 

Marston SA, Polli JE. Evaluation of direct curve comparison metrics applied to pharmacokinetic profiles and relative bioavailability and bioequivalence. Pharm Res 1997 14 1363-1369. 

Much remains to be done to improve the physicochemical properties and the pharmacokinetic characteristics of the estabhshed compound classes. A critical observer cannot help but wonder about the PK/PD profiles of many of the compoimds currently undergoing chnical development with hmited oral bioavailability, often necessitating intravenous administration, and rather short half fives in combination with often transient acetylation effects, the need for HDAC inhibitors with a more beneficial pharmacokinetic profile seems key. 

The quinolones have long enjoyed a favorable pharmacokinetic profile. They are well absorbed and distributed in body tissues and fluids. A typical dose is between 100 mg and 1 g. The older agents have half-lives under 3 h, but a more typical value is between 4 and 14 h. Protein binding tends to be low to moderate (15-65%), but there are some exceptions such as nahdixic acid (90%) and garenoxacin (80%) (Howe and MacGowan, 2004). Bioavailability ranges from 55 to 100% (Dudley, 2003b). It has been well estabhshed in the hterature that the effectiveness of quinolones can be dramatically reduced if the medication is taken with an antacid. Many antacids are salts of divalent and trivalent cations such as Al " , Ca, and Mg " ". In addition, Fe " , Cu " , Ni " ", Zn " ", and also reduce quinolone activity. All these cations form a chelate with... 

Rectal bioavailability and pharmacokinetics. Serenoa repens extract, administered rectally to 12 healthy male volunteers at a dose of 640 mg/person, produced the mean maximum concentration in plasma of nearly 2.60 (Xg/mL approx 3 hours after administration, with mean value for the area under the curve AUC 10 (Xg/hour/mL. The bioavailability and pharmacokinetic profile were similar to those observed after oral administration. T j occurred approx 1 hour later, and plasma concentration 8 hours after drug administration was still quantified. The drug tolerability was good, and no adverse effect was observed ". Serenoa repens capsules, administered orally at a dose of 160 mg four times daily or rectally 640 mg daily for 30 days to 60 patients with BPH, produced no significant differences in diminu-... 

Atazanavir is an azapeptide PI with a pharmacokinetic profile that allows once-daily dosing. It should be taken with a light meal to enhance bioavailability. Atazanavir requires an acidic medium for absorption and exhibits pH-dependent aqueous solubility therefore, separation of ingestion from acid-reducing agents by at least 12 hours is recommended. Atazanavir is able to penetrate both the cerebrospinal and seminal fluids. The plasma half-life is 6-7 hours, which increases to approximately 11 hours when -administered with ritonavir. The primary route of elimination is biliary atazanavir should not be given to patients with severe hepatic insufficiency. 

Finally, as a specific example, the regioselective esterification of ribavirin (24) deserves to be discussed (Figure 6.6) [83]. This compound is a powerful antiviral agent used to treat hepatitis C. In order to overcome some significant side effects, it has been suggested that its administration in the form of a prodrug might improve its pharmacokinetic profile. Indeed a series of predinical evaluations showed that the alanine ester 24a possesses improved bioavailability. In... 

The high aqueous solubility and largely nonpeptidic character of indinavir may be responsible for the good oral bioavailability, respectable pharmacokinetic profile, and high antiviral activity observed with this compound. Similar to saquinavir and ritonavir, indinavir has been recently approved by the FDA for treatment of AIDS. 

Linezolid (2) has a desirable pharmacokinetics profile. Its mean absolute bioavailability is about 100% and its peak plasma concentrations (Umax) are achieved in 1... 

Vigabatrin is rapidly and completely absorbed after oral administration and about 80% of the dose is recovered in the urine [4]. In healthy volunteers, its absorption was rapid and beak plasma concentrations occurred within 2 h [65]. The effect of food on the bioavailability of vigabatrin tablets has been studied [4, 66]. The AUC for fasted and fed volunteers was not significantly different. This indicates that food does not alter the extent of absorption. The pharmacokinetics profiles of vigabatrin in tablet form and in solution were strikingly similar [66]. 

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