The Absorption and Excretion of Paludrine in the Human Subject

Maegraith, B. G.; Tottey, Mary M.; Adams, Arthur; Andrews, W. H. H.; King, Joshua D.

doi:10.1080/00034983.1946.11685302

Cited by 40 publications

(13 citation statements)

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“…Concentrations of the metabolite 4-chlorophenylbiguanide in the present study were also approximately four times higher in whole blood compared with plasma. In contrast the active antimalarial metabolite cycloguanil was not concentrated in red (Maegraith et al, 1946;Ritschel et al, 1978), 12 (Taylor et al, 1984) and 17 (Edstein, 1986) h and a cycloguanil activity terminal half-life of 11 h derived from bioassay (Watkins et al, 1987). This supports prescription of the drug on a daily basis.…”

Section: Discussionmentioning

confidence: 60%

“…Whole blood concentrations were approximately five times higher than the corresponding plasma concentrations. Maegraith et al (1946) estimated that between 73 and 79% of the proguanil in blood was concentrated in erythrocytes, 14% in leucocytes and the remaining 7 to 13% remained in the plasma. Red cell concentrations of antimalarial drugs are of therapeutic importance as the parasite is intraerythrocytic.…”

Section: Discussionmentioning

confidence: 99%

“…The disposition of proguanil in man was investigated shortly after the discovery of its antimalarial activity (Maegraith et al, 1946). Using a non-specific assay, these workers measured plasma concentration profiles after single oral doses ranging from 50 to 500 mg, determined steady state plasma and urine concentrations during 'therapeutic courses' of proguanil (50 or 500 mg twice daily), and described the disposition of the drug after intravenous injection (20 mg).…”

Section: Discussionmentioning

confidence: 99%

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Single dose pharmacokinetics of proguanil and its metabolites in healthy subjects.

Wattanagoon

Taylor

Moody

et al. 1987

Brit J Clinical Pharma

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Hospital, Headington, Oxford OX3 9DU 1 Plasma and whole blood concentrations of proguanil and its two major metabolites cycloguanil (CG) and 4-chlorophenylbiguanide (CPB) were measured by a sensitive h.p.l.c. technique in nine healthy adult male volunteers after a single oral dose of proguanil 200 mg.2 Proguanil was absorbed with a median time to peak plasma concentration of 3 h (range 2-4 h).3 Peak plasma concentrations of proguanil ranged between 150 and 220 (median 170) ng ml-' compared with 12 to 69 (median 41) ng ml-' for the active antimalarial metabolite CG, and 3 to 16 (median 11) ng ml-' for CPB. Peak (mean ± s.d.) plasma CG concentrations occurred 5.3 ± 0.9 h and peak CPB concentrations occurred 6.3 ± 1.4 h after oral administration of proguanil. 4 Whole blood concentrations of proguanil were approximately five times higher, and whole blood CPB concentrations were four times higher than corresponding plasma values, whereas plasma and whole blood concentrations of CG were similar. 5 A triexponential function was fitted to these data; mean (± s.d.) values for the AUC were 3046 ± 313 ng ml-' h for proguanil, 679 ± 372 ng ml-' h for CG and 257 ± 155 ng ml-1 h for CPB. 6 Plasma and whole blood concentrations of proguanil and its metabolites declined in parallel with terminal elimination half-lives estimated as 16.1 ± 2.9 h and 15.7 + 2.4 h, respectively. Mean residence times in plasma and whole blood were estimated as 21.2 ± 4.9 and 19.3 ± 2.4 h.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Single dose pharmacokinetics of proguanil and its metabolites in healthy subjects.

Wattanagoon

Taylor

Moody

et al. 1987

Brit J Clinical Pharma

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“…A small proportion (about 5%) of the proguanil dose is N-dealkylated to 4-chlorophenylbiguanide [ 191. It is possible that the remainder of the dose represents (i) unabsorbed proguanil, as Maegraith et al [24] found 10% of a 100mg oral dose in faeces as proguanil, (ii) intestinal or biliary elimination of proguanil or cycloguanil, (iii) minor residual renal excretion of proguanil and cycloguanil. It is not known whether cycloguanil is further metabolised.…”

Section: -35%mentioning

confidence: 99%

Pharmacokinetic evaluation of proguanil: a probe phenotyping drug for the mephenytoin hydroxylase polymorphism

Somogyi

Reinhard

Bochner

1996

Brit J Clinical Pharma

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Proguanil (PG) oxidative metabolism to cycloguanil (CG) has been linked to the CYP2C 19-mediated genetic polymorphism in S-mephenytoin oxidative metabolism. In many countries, rac-mephenytoin can no longer be administered to humans and hence proguanil may be a more suitable probe for phenotyping purposes. There are limited data on the pharmacokinetics of PG and CG and in particular,whether there is a relationship between the urinary metabolic ratio of PG and its partial intrinsic clearance to CG. The disposition of a 100mg oral dose of PG was investigated in 10 subjects with widely varying metabolic ratios (pre-study urinary metabolic ratio CG to PG =0.068 to 1.1 1 ). Blood samples and all urine were collected for 96 h and assayed for PG and CG by h.p.1.c. The urinary recovery of PG ranged from 30 to 69% of the dose and for CG from 2.8 to 32% of the dose. The overall urinary recovery of PG plus CG ranged from 54 to 77% of the dose. The AUC for PG ranged from 3.2 to 9.5 mg 1-l h whereas for CG it was from 0.02 to 0.71 mg 1-l h. The partial intrinsic clearance to CG ranged 25-fold from 0.41 to 10.1 1 h-l.There was a highly significant (r2 = 0.96, P < 0.001) relationship between the urinary metabolic ratio for PG (as CG/PG) and its partial intrinsic clearance to CG. These data have provided evidence for the justification of the use of the urinary metabolic ratio of proguanil for population phenotyping purposes, provided systematic variation in renal drug clearance between populations is considered.

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“…The elucidation of the pharmacokinetic characteristic of proguanil is therefore necessary if its continued use and potency is not to be forfeited. The determination of proguanil, titrimetically (Stagg, 1947;Gallo et al, 1955) gravimetrically (Green and Babru, 1972) and colorimetrically (Meagraith et al, 1946) and microbially (Smith et al, 1961) are lacking both in specificity and sensitivity and are therefore of no use for the pharmacokinetic study on proguanil. There are however a few chromatographic methods with the advantage of specificity and sensitivity.…”

Section: Introductionmentioning

confidence: 99%

High performance liquid chromatographic determination of proguanil after derivatisation with sodium benzoxazole-2-sulphonate

Adewuyi¹,

Olubomehin²,

Ayanniyi³

2010

Afr. J. Biotechnol.

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A simple, fast and reproducible method for the determination of proguanil using high performance liquid chromatographic with UV/Fluorescence detection is described. Proguanil was derivatised to its corresponding derivative [(N 1 -(4-chlorophenyl)-N 5 -(1 -methyl ethyl) imidocarbonimideamide-Nbenzoxazole]. The derivatisation reaction was conducted in methanol at 60°C using sodium benzoxazole-2-sulphonate under alkaline conditions. The resulting derivative was extracted with chloroform after which the extract was observed under UV lamp at 254 nm before TLC and HPLC analysis. Similarly, the derivatisation process was adapted for derivatisation of proguanil in urine sample. The reaction proceeded smoothly and rapidly. The extraction process was not cumbersome and eliminated the need for costly extraction and evaporation equipments. The resulting derivative fluorensced intensely under UV lamp. Direct HPLC analysis of the reaction mixture was found possible without interferences from excess reagent and endogeneous compounds like ammonium salts. The derivative eluted in less than seven minutes thus making the method suitable for routine use. The calibration plot was linear over the concentration range. A correlation regression of the order of 0.94 was obtained from the calibration curve which indicated a strong relationship between the instrument response and the concentration of proguanil. The discussion also summarizes the derivatisation chemistry that have not being fully explored to date but may find utility in future development of highly sensitive analytical methods for biquanide drugs.

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The Absorption and Excretion of Paludrine in the Human Subject

Cited by 40 publications

References 13 publications

Single dose pharmacokinetics of proguanil and its metabolites in healthy subjects.

Single dose pharmacokinetics of proguanil and its metabolites in healthy subjects.

Pharmacokinetic evaluation of proguanil: a probe phenotyping drug for the mephenytoin hydroxylase polymorphism

High performance liquid chromatographic determination of proguanil after derivatisation with sodium benzoxazole-2-sulphonate

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