Pharmacokinetics in vivo

A clear priority remains to expand the panel of intestinal efflux transporters that are expressed individually in modified cell lines. These research tools will be instrumental in identifying and validating selective probe transporter substrates and inhibitors. The availability of such probes will allow for a better understanding of the influence of transporters on in vivo pharmacokinetics. A similar set of probes has been instrumental in increasing our understanding of the role that cytochrome P450 plays in human pharmacokinetics and in avoiding issues associated with these enzymes. 

Beaudry F. et al., 1998. In vivo pharmacokinetic screening in cassette dosing experiments Use of online Pros-pekt liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry technology in drug discovery. Rapid Commun Mass Spectrom 12 1216. 

In this section the in vitro reactivity of various octahedral complexes of technetium and rhenium are discussed and correlated with the in vivo pharmacokinetic data as observed for currently used radiopharmaceutical agents, which in most cases are indeed octahedral complexes of these metal centers. 

Tracy, T.S. (2003) Atypical enzyme kinetics their effect on in vitro-in vivo pharmacokinetic predictions and drug interactions. Current Drug Metabolism, 4 (5), 341-346. 

In addition, compound 15 also had good metabolic stability in human liver microsome in vitro assay (hLM ti/2 = 39min) and in rat in vivo pharmacokinetic studies (ty2 = 3.3 h, po), with a rat oral bioavailability of 15%, showing a significant improvement in these PK parameters over the lead compound 1. The observed improvement in PK during the optimization was another validation of the strategy discussed above. This part of the optimization process is summarized in Scheme 19.2. 

One challenge that remains in biopharmaceutics research is that of correlating in vitro drug-release profiles with the in vivo pharmacokinetic data. TVIVC has been defined by the... 

Tannergren C, Evilevitch L, Pieyzynowski S, Piedra JV, Westrom B, Erlwanger K, Tatara M and Lennernas H (2006) The Effect of Pancreatic and Biliary Depletion on In Vivo Pharmacokinetics of Digoxin in Pigs. EurJ Pharm Sci 29 pp 198-204. 

It appears that qualitative correlations between antibacterial activity and rate constants of HO ion catalyzed hydrolysis are fortuitous since many factors other than transpeptidase acylation contribute to antimicrobial activity. These other contributing factors include permeation of the outer membrane of the bacterial cell wall, resistance to /3-lactamase, the fit in the active site of the enzyme, stability of the acylated enzyme, and, last but not least, in vivo pharmacokinetic behavior. 

The results of the in vivo pharmacokinetics are shown in Table 1. DCM-Dex/CDDP conjugate had a significantly longer Pt half-life in the blood after intravenous injection than free CDDP or the OX-Dex/CDDP conjugate. 

Walton, K., J.L. Dome, and A.G. Renwick. 2001a. Uncertainty factors for chemical risk assessment Interspecies differences in the in vivo pharmacokinetics and metabolism of human CYP1A2 substrates. Food Chem. Toxicol. 39 667-680. 

Aboagye EO, Price PM, Jones T. In vivo pharmacokinetics and pharmacodynamics in drug development using positron-emission tomography. Drug Discov Today 2001 6 293 02. 

The ADME portion of the BioPrint profile is made up of a panel of in vitro assays chosen for their potential to predict in vivo pharmacokinetics (Table 2). Some of the in vitro assays measure properties that contribute to the in vivo bioavailability of the new drug candidate. These include aqueous solubility, log D (octanol), and log D (cyclohexane), physico-chemical... 

In vitro and in vivo pharmacokinetic studies with tretinoin cream and gel indicated that less than 0.3% of the topically applied dose is bioavailable. Circulating plasma levels of tretinoin are only slightly elevated above those found in healthy normal controls. Estimates of in vivo bioavailability ot Retin-A M/cro following single and multiple daily applications, for a period of 28 days with the 0.1 % gel, were... 

Cerep evaluates hits, leads, and new compounds from the metabolic point of view using liver microsomes and recombinant cytochrome P450s (275). The results of these metabolic screening studies offer insight to the rate of metabolic pathways, in vivo pharmacokinetic properties, and drug-drug interactions. 

Some caution is required with some chemical classes and compound properties related to low solubility, high lipophihcity, major impact of active transport processes on elimination and distribution. It is therefore recommended that PBPK models should only be applied after verification of the simulations with in vivo pharmacokinetics for a few compounds of a given chemical class. Such verification will help to identify invalid model assumptions or missing processes where additional data is needed. 

Schmider J, von Moltke LL, Shader Rl, et al. Extrapolating in vitro data on drug metabolism to in vivo pharmacokinetics evaluation of the pharmacokinetic interaction between amitriptyline and fluoxetine. Drug Metab Rev 1999 31 545-560. 

Maximal plasma concentrations occur 2 to 3 hours after oral administration of reboxetine (178). Reboxetine has linear pharmacokinetics over its clinically relevant dosing range and a half-life of approximately 12 hours. For this latter reason, a twice a day, equally divided dosing schedule was used during clinical trial development. Its clearance is reduced and half-life becomes longer as a function of advanced age (mean = 81 years of age) and renal and hepatic impairment ( 178, 322, 323). Reboxetine is principally metabolized by CYP 3A3/4 such that its dose should be reduced when used in combination with drugs that are substantial inhibitors of CYP (e.g., certain azole antifungals, certain macrolide antibiotics). Reboxetine itself, however, does not cause detectable inhibition of CYP 3A3/4 based on formal in vivo pharmacokinetic interaction studies as well as its own linear pharmacokinetics. 

Thus, FUB 307 (42) may be regarded as a kind of retard prodrug and represents the first reported compound of the azomethine prodrug type and particularly the first histamine H3 receptor agonist to possess such prolonged in vivo pharmacokinetics [45],... 

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