Gallopamil binding to human serum proteins

Rutledge, David R.; Pieper, John A.

doi:10.1007/bf00637633

Cited by 7 publications

(4 citation statements)

References 18 publications

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“…Previous studies have already documented this phenomenon, e.g. propranolol (Ravis et al, 1987), phencyclidine (Owens et al, 1983), gallopamil (Rutledge & Pieper, 1987) and prilocaine (Bachmann et al, 1990). The possibility that the variation in ligand binding could be due to pH-induced changes in the protein is rendered unlikely by the behaviour of darodipine and isradipine, un-ionizable ligands whose affinities remain constant in the pH range 6.8-8.0.…”

Section: Discussionmentioning

confidence: 92%

pH-dependency of basic ligand binding to α1-acid glycoprotein (orosomucoid)

Urien

Brée

Testa

et al. 1991

Biochemical Journal

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The binding interactions of a series of basic ligands with alpha 1-acid glycoprotein (AAG) were examined as a function of pH. The binding to AAG increased with increasing pH, and the binding data were satisfactorily fitted to a model that incorporates the effect of pH and discriminates the association constants of neutral (non-protonated) and protonated forms of ligands. It was shown that ligands in the neutral form have a markedly higher affinity for AAG than the protonated forms, resulting in a concomitant decrease in the pKa of bound ligands. The u.v.-visible difference spectra generated upon binding of a representative ligand to AAG also showed that there was a contribution to the binding arising from the deprotonation of the ligand. It is suggested that all tested ligands bind similarly to AAG and that hydrophobic interactions dominate high-affinity binding to AAG.

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Section: Discussionmentioning

confidence: 92%

pH-dependency of basic ligand binding to α1-acid glycoprotein (orosomucoid)

Urien

Brée

Testa

et al. 1991

Biochemical Journal

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“…In order to evaluate data obtained with different drugs or to predict effects from in vitro to in vivo the free concentrations of the drugs or the tissue levels should be corn- Protein binding. The six calcium channel antagonists studied here are all extensively bound to human plasma proteins: NIF 99% (Otto and Lesko 1986), NIT 98% (Eichelbaum et al 1986), NIM 99% (drug information), VER about 90% (Keefe et al 1981;McGowan et al 1983), GAL 93% (Rutledge and Pieper 1987), DIL about 80% (Morselli et al 1979;Bloedow et al 1980;Kwong et al 1985).…”

Section: Unsolved Problems and Drawbacks When Attempting Extrapolatiomentioning

confidence: 98%

Effects of calcium channel blockers on the development of early rat postimplantation embryos in culture

et al. 1990

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Rat embryos (9.5-day-old) were cultured for 48 h in the presence of nifedipine (NIF), nimodipine (NIM), nitrendipine (NIT), gallopamil HCl (GAL), verapamil HCl (VER) and diltiazem HCl (DIL). The effects on growth and morphogenetic differentiation in vitro were monitored. Dose-response relationships were evaluated, including an assessment of the "no-observed-effect-level" (NOEL) or the "lowest-observed-effect-level" (LOEL), and the lowest concentration tested inducing abnormalities in 100% of the embryos ("100% EL"). The morphological alterations observed at the highest concentrations were very similar for all six drugs. The abnormalities concerned yolk sac circulation and morphology, as well as heartbeat, the morphology of the heart, head, neural tube, or forelimbs, and the shape of the embryo. The abnormal embryos were also growth retarded (decrease in protein content and crown-rump length). Interference with calcium channel functions seems to represent an interesting model for studying a special kind of abnormal prenatal development, especially the differentiation of certain mesenchymal structures. The concentration ranges between NOELs and 100% ELs were found to be: NIM = 0.1-1 microgram/ml; NIT and VER = 1-10 micrograms/ml; DIL = 1-30 micrograms/ml, and LOELs-100% ELs were: GAL = 1-10 micrograms/ml; NIF = 10-30 micrograms/ml.

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“…l4 Extensive binding of gallopamil has been observed in serum from healthy volunteers cf;: 0.075 2 0.007). 15 In serum, two classes of binding sites have been described and studies using isolated proteins suggest that the high affinity binding site is the acute phase protein a,-acid glycoprotein, and the lower aftinity binding site is albumin. 15 The present study was initiated to determine whether the binding of the enantiomers of gallopamil to albumin, a,-acid glycoprotein, and total serum protein is enantioselective.…”

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confidence: 99%

Enantioselective gallopamil protein binding

et al. 1993

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The protein binding of the enantiomers of gallopamil has been investigated in solutions of human serum albumin, alpha 1-acid glycoprotein and serum. Over the range of concentrations attained after oral gallopamil administration, the binding of both enantiomers to albumin, alpha 1-acid glycoprotein, and serum proteins was independent of gallopamil concentration. The binding to both human serum albumin (40 g/liter) [range of fraction bound (fb) R: 0.624 to 0.699; S: 0.502 to 0.605] and alpha 1-acid glycoprotein (0.5 g/liter) (range of fb R: 0.530 to 0.718; S: 0.502 to 0.620) was stereoselective, favoring the (R)-enantiomer (predialysis gallopamil concentrations 2.5 to 10,000 ng/ml). When the enantiomers (predialysis gallopamil concentration 10 ng/ml) were studied separately in drug-free serum samples from six healthy volunteers the fraction of (S)-gallopamil bound (fb: 0.943 +/- 0.016) was lower (P < 0.05) than that of (R)-gallopamil (fb: 0.960 +/- 0.010). The serum protein binding of both (R)- and (S)-gallopamil was unaffected by their optical antipodes (fb R: 0.963 +/- 0.011; S: 0.948 +/- 0.015) indicating that at therapeutic concentrations a protein binding enantiomer-enantiomer interaction does not occur. The protein binding of (R)- and (S)-gallopamil ex vivo 2 h after single dose oral administration of 50 mg pseudoracemic gallopamil (fb R: 0.960 +/- 0.010: predialysis [R] 6.9 to 35.3 ng/ml; S: 0.943 +/- 0.016: predialysis [S] 9.5 to 30.7 ng/ml) was comparable to that observed in vitro in drug-free serum. Gallopamil metabolites formed during first-pass following oral administration, therefore, do not influence the protein binding of (R)- or (S)-gallopamil.

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Gallopamil binding to human serum proteins

Cited by 7 publications

References 18 publications

pH-dependency of basic ligand binding to α1-acid glycoprotein (orosomucoid)

pH-dependency of basic ligand binding to α1-acid glycoprotein (orosomucoid)

Effects of calcium channel blockers on the development of early rat postimplantation embryos in culture

Enantioselective gallopamil protein binding

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