Steady-State Kinetics of Proguanil and Its Active Metabolite, Cycloguanil, in Man

Edstein, Michael D.; Veenendaal, J.R.; Scott, H. V.; Rieckmann, Karl H.

doi:10.1159/000238597

Cited by 17 publications

(5 citation statements)

References 11 publications

(17 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our observation that the mean urinary recovery of PG was about 22% of dose regardless of phenotype (Table 2) is consistent with that of previous studies [23,24] indicating that renal clearance of PG accounted for about 25% of its total clearance. For instance, Wattanagoon et al [24] showed that the mean (± s.d.…”

Section: Discussionsupporting

confidence: 92%

“…mean) total clearance of PG was 19.1 ± 2.8 ml minkg-l with a renal clearance of 5.0 ± 1.9 ml min-' kg-' in 10 healthy subjects. In addition, these studies [23,24] suggested that a substantial proportion (up to 60% of dose) of plasma PG clearance remains unaccounted for. In this context, our total 12 h urinary recovery (i.e., PG + CG + CPB) was about 32% in EMs and 23% in PMs.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Metabolic disposition of proguanil in extensive and poor metabolisers of S‐mephenytoin 4'‐hydroxylation recruited from an Indonesian population.

Setiabudy

Kusaka

Chiba

et al. 1995

Brit J Clinical Pharma

View full text Add to dashboard Cite

1 The metabolism of proguanil (PG) was studied by measuring PG, cycloguanil (CG) and 4-chlorophenylbiguanide (CPB) in plasma and urine samples after an oral 200 mg dose of PG hydrochloride administered to 14 extensive (EMs) and 10 poor hydroxylators (PMs) of S-mephenytoin of Indonesian origin.2 The mean (± s.d.) values of the elimination half-life (ti/2) and AUC of PG were significantly (P < 0.01) greater in the PM than in the EM group (20.6 ± 3.1 vs 14.6 ± 3.5 (95% confidence intervals of difference 3.1 to 8.9) h; and 5.43 ± 1.89 vs 3.68 ± 0.83 (0.58 to 2.91) gg ml-1 h).3 Plasma concentrations of CG, an active metabolite, could not be detected in all PMs, and those of CPB were sufficiently high to determine a time-course in only four PMs. Mean AUC(0,24 h) values of CPB were significantly (P < 0.05) lower in the PM (n = 4) than in the EM group (n = 14) (0.47 ± 0.13 vs 0.88 ± 0.50 (-0.14 to 0.96) ,ug ml-1 h). (rs = -0.831) metabolic ratios.6 The bioactivation of PG to CG cosegregates with the genetically determined 4'-hydroxylation polymorphism of S-mephenytoin in Indonesian subjects, and the formation of CPB appears to be associated partially with S-mephenytoin 4'-hydroxylation.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Metabolic disposition of proguanil in extensive and poor metabolisers of S‐mephenytoin 4'‐hydroxylation recruited from an Indonesian population.

Setiabudy

Kusaka

Chiba

et al. 1995

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…[14] In vivo, proguanil activation to cycloguanil is a minor metabolic pathway with 11.2 ± 4.2% of the dose excreted in urine as cycloguanil [23]. Renal clearance of proguanil accounts for about 25% of total clearance [23,24].…”

Section: Discussionmentioning

confidence: 99%

In vitro proguanil activation to cycloguanil by human liver microsomes is mediated by CYP3A isoforms as well as by S‐mephenytoin hydroxylase.

Birkett

Rees

Andersson

et al. 1994

Brit J Clinical Pharma

View full text Add to dashboard Cite

1. The activation of proguanil to cycloguanil by human liver microsomes was studied to define the cytochrome P450 (CYP) isoforms involved in this reaction. 2. Apparent Km values for proguanil ranged from 35 microM to 183 microM with microsomes from four human livers. 3. There was a 6.3‐fold range of activity with microsomes from seventeen human livers. Rates of proguanil activation correlated significantly with CYP3A activities (benzo[a]pyrene metabolism, caffeine 8‐oxidation and omeprazole sulphone formation) and CYP3A immunoreactive content. There was also a highly significant correlation with rates of hydroxyomeprazole formation. Correlations with activities selective for CYP1A2, CYP2C9/10 and CYP2E1, and with immunoreactive CYP1A2 content were not significant. 4. Proguanil activation was inhibited by R,S‐ mephenytoin, troleandomycin and by inhibitory anti‐CYP3A antiserum and anti‐CYP2C IgG and was activated by alpha‐naphthoflavone. Inhibitors selective for CYP1A2, CYP2E1, CYP2A6 or CYP2C9/10 had little or no effect on proguanil activation. The extents of inhibition by R,S‐ mephenytoin, troleandomycin and the two antibodies varied with the immunoreactive CYP3A content of the microsomes used. 5. It is concluded that proguanil activation to cycloguanil by human liver microsomes is mediated both by S‐mephenytoin hydroxylase and isoforms of the CYP3A subfamily. This has implications for the use of proguanil as an in vivo probe for the S‐mephenytoin poor metaboliser phenotype.

show abstract

“…When comparing the kinetic data of the same individuals following the adminis tration of proguanil alone [16] and pro guanil/dapsone, a significant difference was found in the elimination halflife of PROG which was longer in the combina tion study (18.313.0 h versus 14.513.0 h, p = 0.013). There was, however, no signifi cant difference in the plasma clearance of PROG and in the estimated kinetic values (Cm aX) t/; and AUC) of CYCLO following dosing with proguanil alone and in combi nation with dapsone.…”

Section: Discussionmentioning

confidence: 97%

Multiple-Dose Kinetics in Healthy Volunteers and in vitro Antimalarial Activity of Proguanil plus Dapsone

Edstein¹,

Veenendaal²,

Rieckmann³

1990

Chemotherapy

Self Cite

View full text Add to dashboard Cite

The multiple-dose kinetics of a daily dose of proguanil (200 mg) coadministered with dapsone (10 mg) was investigated in 6 healthy adult male volunteers. The kinetics of dapsone (DDS), monoacetyldapsone (MADDS), proguanil (PROG) and its active metabolite cycloguanil (CYCLO) were derived from plasma drug concentrations after the last maintenance dose. The following kinetic parameters (mean values) were estimated for DDS and PROG, respectively: maximum concentration (C_max) = 285 and 151 ng/ml, minimum concentration (C_min) = 125 and 31 ng/ml, elimination half-life (t._½) = 23.3 and 18.3 h, plasma clearance (CI) = 0.032 and 1.27 1/h/kg and apparent volume of distribution (V_ss) = 1.05 and 33.32 1/kg. The C_max, Cmin and t_½ of CYCLO were 56 ng/ml, 17 ng/ml and 15.0 h, respectively. The antimalarial activity of the proguanil/ dapsone combination was assessed in vitro by measuring the inhibition of re-invasion of two Plasmodium falciparum isolates grown in the presence of volunteers’sera. Both FC-27 [chloroquine (CQ) and pyrimethamine (PYR)-sensitive] and Kl (CQ- and PYR-resistant) isolates were completely inhibited by the drug combination at steady-state concentrations. These findings suggest that the drug regimen may be effective against drug-resistant falciparum malaria.

show abstract

Steady-State Kinetics of Proguanil and Its Active Metabolite, Cycloguanil, in Man

Cited by 17 publications

References 11 publications

Metabolic disposition of proguanil in extensive and poor metabolisers of S‐mephenytoin 4'‐hydroxylation recruited from an Indonesian population.

Metabolic disposition of proguanil in extensive and poor metabolisers of S‐mephenytoin 4'‐hydroxylation recruited from an Indonesian population.

In vitro proguanil activation to cycloguanil by human liver microsomes is mediated by CYP3A isoforms as well as by S‐mephenytoin hydroxylase.

Multiple-Dose Kinetics in Healthy Volunteers and in vitro Antimalarial Activity of Proguanil plus Dapsone

Contact Info

Product

Resources

About