Comparison of disposition parameters of quinidine and quinine in the rat.

Watari, Nobutoshi; Wakamatsu, Akira; Kaneniwa, Nobuyoshi

doi:10.1248/bpb1978.12.608

Cited by 11 publications

(3 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The increase in Vd in the case of quinine is difficult to explain. There are pharmacokinetic differences between quinine and quinidine in the rat (Watari et a1 1989), and in their binding properties to various components within the body (Kurz & Fichtl 1983;Mihaly et a1 1987b;Watari et al 1989). These present studies demonstrate that neither drug accumulates in the highly perfused organs such as the heart and the liver and is in agreement with earlier works investigating their distribution pattern in various tissues in fowl and dog (Kelsey et a1 1943;Hiatt & Quinn 1945).…”

Section: Discussionsupporting

confidence: 91%

The Effect of Fever on Quinine and Quinidine Disposition in the Rat

Mansor

Ward

Edwards

1991

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

The pharmacokinetics of quinine and its diastereoisomer quinidine has been investigated in normal and febrile rats. Endotoxin-induced fever in rats resulted in an increased quinine clearance (CL) (4.49 +/- 1.45 vs 1.38 +/- 0.65 L h-1 kg-1, P less than 0.001) and volume of distribution (Vd) (42.6 +/- 8.8 vs 28.9 +/- 10.3 L kg-1, P less than 0.05) with a concomitant shortening of the elimination half-life (t1/2) (7.1 +/- 2.5 vs 15.9 +/- 5.9 h, P less than 0.01). With quinidine, however, fever resulted in an increased CL (3.95 +/- 1.05 vs 1.89 +/- 0.60 L h-1 kg-1, P less than 0.002) with no change in Vd and a significant decrease in t1/2 (5.1 +/- 0.7 vs 10.1 +/- 2.8 h, P less than 0.001). In both studies there was no significant difference in hepatic microsomal protein or cytochrome P450 content. Neither drug accumulated in the liver but low concentrations of quinidine were present in the heart 24 h after administration. In-vitro studies suggest that temperature does not alter the binding of either drug. These data suggest that fever enhances the clearance of quinine and quinidine. These findings may offer some additional explanation of the lack of serious quinine and quinidine toxicity during the treatment of malaria infection, even after large dosages of the drug administered during the initial period of treatment when fever is most intense.

show abstract

Section: Discussionsupporting

confidence: 91%

The Effect of Fever on Quinine and Quinidine Disposition in the Rat

Mansor

Ward

Edwards

1991

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

show abstract

“…For human plasma a 3-fold increase of unbound fraction with increasing concentrations was reported . Also rat plasma protein binding increased with quinidine concentration . As the fraction unbound is important for the calculation of K p,uu , we investigated the PPB for quinidine at 4 μM, the steady state target concentration in this infusion study.…”

Section: Methodsmentioning

confidence: 99%

“…31 Also rat plasma protein binding increased with quinidine concentration. 33 As the fraction unbound is important for the calculation of K p,uu , we investigated the PPB for quinidine at 4 μM, the steady state target concentration in this infusion study. Dialysis was carried out for 2 h under rotation at 37 °C.…”

Section: Molecular Pharmaceuticsmentioning

confidence: 99%

Quantification of Transporter and Receptor Proteins in Dog Brain Capillaries and Choroid Plexus: Relevance for the Distribution in Brain and CSF of Selected BCRP and P-gp Substrates

et al. 2017

View full text Add to dashboard Cite

Transporters at the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) play a pivotal role as gatekeepers for efflux or uptake of endogenous and exogenous molecules. The protein expression of a number of them has already been determined in the brains of rodents, nonhuman primates, and humans using quantitative targeted absolute proteomics (QTAP). The dog is an important animal model for drug discovery and development, especially for safety evaluations. The purpose of the present study was to clarify the relevance of the transporter protein expression for drug distribution in the dog brain and CSF. We used QTAP to examine the protein expression of 17 selected transporters and receptors at the dog BBB and BCSFB. For the first time, we directly linked the expression of two efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), to regional brain and CSF distribution using specific substrates. Two cocktails, each containing one P-gp substrate (quinidine or apafant) and one BCRP substrate (dantrolene or daidzein) were infused intravenously prior to collection of the brain. Transporter expression varied only slightly between the capillaries of different brain regions and did not result in region-specific distribution of the investigated substrates. There were, however, distinct differences between brain capillaries and choroid plexus. Largest differences were observed for BCRP and P-gp: both were highly expressed in brain capillaries, but no BCRP and only low amounts of P-gp were detected in the choroid plexus. K and K of both P-gp substrates were indicative of drug efflux. Also, K for the BCRP substrates was low. In contrast, K for both BCRP substrates was close to unity, resulting in K/K ratios of 7 and 8, respectively. We conclude that the drug transporter expression profiles differ between the BBB and BCSFB in dogs, that there are species differences in the expression profiles, and that CSF is not a suitable surrogate for unbound brain concentrations of BCRP substrates in dogs.

show abstract