Timolol and propranolol: Bioavailability, plasma concentrations, and beta blockade

Wilson, Thomas W.; Firor, W.B.; Johnson, Guy; Holmes, Geoffrey I; Tsianco, Michael C; Huber, Paul B; Davies, Richard O.

doi:10.1038/clpt.1982.223

Cited by 38 publications

(12 citation statements)

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“…IBU and TIM, which have a high F in humans [100% (Martin et al, 1990) and 61.0% (Wilson et al, 1982), respectively], as well as AMI and PRO, which have a moderate F in humans [47.7% (Schulz et al, 1983) and 29.0% (Borgstrom et al, 1981), respectively], were assigned to this category. See Table 1 for P450 isozymes that contribute to each drug metabolism.…”

Section: Methodsmentioning

confidence: 99%

A Comparison of Pharmacokinetics between Humans and Monkeys

Akabane¹,

Tabata²,

Kadono³

et al. 2009

Drug Metab Dispos

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ABSTRACT:To verify the availability of pharmacokinetic parameters in cynomolgus monkeys, hepatic availability (Fh) and the fraction absorbed multiplied by intestinal availability (FaFg) were evaluated to determine their contributions to absolute bioavailability (F) after intravenous and oral administrations. These results were compared with those for humans using 13 commercial drugs for which human pharmacokinetic parameters have been reported. In addition, in vitro studies of these drugs, including membrane permeability, intrinsic clearance, and p-glycoprotein affinity, were performed to classify the drugs on the basis of their pharmacokinetic properties. In the present study, monkeys had a markedly lower F than humans for 8 of 13 drugs. Although there were no obvious differences in Fh between humans and monkeys, a remarkable species difference in FaFg was observed. Subsequently, we compared the FaFg values for monkeys with the in vitro pharmacokinetic properties of each drug. No obvious FaFg differences were observed between humans and monkeys for drugs that undergo almost no in vivo metabolism. In contrast, low FaFg were observed in monkeys for drugs that undergo relatively high metabolism in monkeys. These results suggest that first-pass intestinal metabolism is greater in cynomolgus monkeys than in humans, and that bioavailability in cynomolgus monkeys after oral administration is unsuitable for predicting pharmacokinetics in humans. In addition, a rough correlation was also observed between in vitro metabolic stability and Fg in humans, possibly indicating the potential for Fg prediction in humans using only in vitro parameters after slight modification of the evaluation system for in vitro intestinal metabolism.Because the development of new drugs is a cost-and labor-intensive task, the selection of candidates with good pharmacokinetic profiles is becoming increasingly common. This practice minimizes the number of drug candidates dropped due to pharmacokinetic problems during the clinical phase (Wishart, 2007).When predicting human pharmacokinetics, the fraction absorbed (Fa), intestinal availability (Fg), and hepatic availability (Fh) are the main factors to consider. Fh prediction has become considerably accurate since several mathematical prediction models have been established, including the physiological model, well stirred model, parallel tube model, and dispersion model (Iwatsubo et al., 1996;Naritomi et al., 2001;De Buck et al., 2007). For FaFg, however, no quantitative prediction method has ever been established, although several qualitative prediction methods using human intestinal microsomes have been reported (Chiba et al., 1997;Shen et al., 1997;Fagerholm, 2007;Fisher and Labissiere, 2007;Yang et al., 2007). For these reasons, we have mainly used animal pharmacokinetic parameters to predict human FaFg in the drug discovery stage.It has been regarded as natural that monkey metabolism is the most similar to that of humans, and cynomolgus monkeys have been widely used in pharmacokinetic or drug-...

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Section: Methodsmentioning

confidence: 99%

A Comparison of Pharmacokinetics between Humans and Monkeys

Akabane¹,

Tabata²,

Kadono³

et al. 2009

Drug Metab Dispos

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“…It is a chiral compound (R,S-Prop) and the ␤-blocking activity is produced by the S-enantiomer while both enantiomers possess equal membrane stabilizing effect [6]. Numerous achiral methods have been published for the determination of Prop in human fluids [7][8][9][10][11][12] as well as several enantioselective assays using chiral stationary phases (CSPs). The measurement of R-and S-Prop in human serum has been accomplished using a (R-N-(3,5-dinitrobenzoyl)-phenylglycine) CSP [13] and a cellulose-tris(3,5-dimethylphenylcarbamate) CSP [14], the latter method was applied to a pharmacokinetic study of Prop enantiomers in healthy male volunteers [15].…”

Section: Introductionmentioning

confidence: 99%

HPLC–atmospheric pressure chemical ionization mass spectrometric method for enantioselective determination of R,S-propranolol and R,S-hyoscyamine in human plasma

Siluk¹,

Mager²,

Gronich³

et al. 2007

Journal of Chromatography B

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Section: In Vitro-in Vivo Correlation Of Seven Compounds Using 10 Indmentioning

confidence: 99%

“…Naloxone [Asali and Brown (1984); Holford (1998)]; buspirone [Gammans et al (1986)]; verapamil [Gross et al (1988);McAllister and Kirsten (1982); Obach (1999)]; lidocaine [Remmel et al (1991); Wing et al (1984)]; imipramine [the pharmacokinetics were mean value of the report of Ciraulo et al (1988) and Nagy and Johansson (1975)]; metoprolol ; Regardh et al (1974); Regardh et al (1981)]; timolol [Wilson et al (1982), Holford (1998)]; antipyrine [Elfstrom and Lindgren (1978); Vesell et al (1975)]; diazepam [Divoll et al (1983); Greenblatt et al (1980); Maguire et al (1980)]; quinidine [Guentert et al (1979); Hardy and Schentag (1988); Hughes et al (1975)]; caffeine [Blanchard (1982); …”

Section: Profiles Of 14 Compounds Tested With the Pooled Preparation mentioning

confidence: 99%

Prediction of Hepatic Clearance and Availability by Cryopreserved Human Hepatocytes: An Application of Serum Incubation Method

Shibata¹,

Takahashi²,

Chiba³

et al. 2002

Drug Metab Dispos

157

156

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ABSTRACT:A novel and convenient method was established for the prediction of in vivo metabolic clearance in human liver. The present method applied the in vitro-in vivo extrapolation paradigm previously established in rats to the in vitro data obtained from cryopreserved human hepatocytes. Predicted hepatic availability and clearance were compared with the reported oral bioavailability and plasma clearance in humans for 14 clinically used drugs (naloxone, buspirone, verapamil, lidocaine, imipramine, metoprolol, timolol, antipyrine, diazepam, quinidine, caffeine, propranolol, diclofenac, and phenacetin). A large interindividual variation was observed in the intrinsic metabolic clearance among separate cryopreserved preparations from different subjects. The prediction generally resulted in a marked underestimation when the biologically based scaling (cells/kg) from pooled preparation of two selected lots, which were 3-to 4-fold larger than the biologically based scaling factor. These data suggested that the calibration of inherent interindividual variation of metabolic activities among different cryopreserved preparations of human hepatocytes to obtain the empirical scaling factor, which is applicable only to the preparation used, was an essential step for more reliable and quantitative prediction of in vivo metabolic activity in humans.Hepatic clearance for the metabolism of compounds kinetically consists of two major determinants: intrinsic (metabolic) clearance of the unbound compound and unbound fraction of compound in the blood (or plasma when corrected by the blood-to-plasma partition). Generally, the intrinsic clearance for the unbound compound is measured in vitro by the incubation of isolated hepatocytes or subcellular fractions such as S-9 and microsomes in the protein-free medium. The in vitro metabolic parameters thus obtained are extrapolated by using anatomical parameters such as cell numbers and protein content in the intact liver for the prediction of in vivo metabolic activity (Houston and Carlile, 1997;Iwatsubo et al., 1997;Obach, 1999). Separate experiments necessarily are further carried out to measure the unbound fraction in the plasma. Many technical problems including adsorption of compounds to the apparatus during the equilibrium dialysis and ultra-filtration often hamper the accuracy of the evaluated values (Bertilsson et al., 1979;Desoye, 1988). To improve the accuracy and avoid complexity for predicting in vivo metabolic clearance from in vitro experiments, we have recently developed a novel and convenient in vitro method for predicting in vivo metabolic clearance by using freshly isolated rat hepatocytes suspended in rat serum (Shibata et al., 2000). Oral bioavailability and hepatic clearance for 16 widely used compounds were well predicted directly from the in vitro metabolic clearance values obtained from a single incubation without separate evaluation of unbound fraction in the plasma. The purposes of the present study were to 1) determine whether the same methodology was applicable ...

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Timolol and propranolol: Bioavailability, plasma concentrations, and beta blockade

Cited by 38 publications

References 0 publications

A Comparison of Pharmacokinetics between Humans and Monkeys

A Comparison of Pharmacokinetics between Humans and Monkeys

HPLC–atmospheric pressure chemical ionization mass spectrometric method for enantioselective determination of R,S-propranolol and R,S-hyoscyamine in human plasma

Prediction of Hepatic Clearance and Availability by Cryopreserved Human Hepatocytes: An Application of Serum Incubation Method

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