Steady state disposition of chloroquine in patients with rheumatoid disease

Frisk-Holmberg, M; Bergqvist, Yngve; Domeij-Nyberg, B

doi:10.1007/bf00607097

Cited by 13 publications

(16 citation statements)

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“…Accordingly, the finding that, in humans, DCQ was readily detectable in plasma during the absorption phase of CQ pointed to an enzymatic system with a high capacity (Ducharme and Farinotti, 1996). The predicted nonrenal clearance value of 0.52 Ϯ 0.04 ml/min/kg estimated from the present HLM investigations is in agreement with the one obtained in vivo from normal subjects (0.63-1.02 ml/min/kg; Frisk-Holmberg et al, 1983;Gustafsson et al, 1983;Ette et al, 1989).…”

Section: Chloroquine N-desethylation By Cyp2c8 Cyp3a4 and Cyp2d6supporting

confidence: 87%

“…DCQ is rapidly detected in blood or plasma, its concentrations amounting to 20 to 50% of those of the parent Frisk-Holmberg et al, 1984). For BDCQ, plasma or blood concentrations never reach more than 10 to 15% of CQ levels (Frisk-Holmberg et al, 1983, 1984Augustjins et al, 1992). Although CQ possesses cytochrome P450 (P450)-inhibiting properties, notably on CYP2D6 (Lancaster et al, 1990;Halliday et al, 1995;Masimirembwa et al, 1995), the enzymes catalyzing its N-dealkylation have never been identified.…”

mentioning

confidence: 99%

“…In humans, the liver and kidneys contribute approximately equally to its body disposition (Frisk-Holmberg et al, 1983;Gustafsson et al, 1983;Ette et al, 1989). Following oral or i.v.…”

mentioning

confidence: 99%

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IN VITRO METABOLISM OF CHLOROQUINE: IDENTIFICATION OF CYP2C8, CYP3A4, AND CYP2D6 AS THE MAIN ISOFORMS CATALYZINGN-DESETHYLCHLOROQUINE FORMATION

Projean

Baune²,

Farinotti³

et al. 2003

Drug Metab Dispos

164

117

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ABSTRACT:In humans, the antimalarial drug chloroquine (CQ) is metabolized into one major metabolite, N-desethylchloroquine (DCQ). Using human liver microsomes (HLM) and recombinant human cytochrome P450 (P450), we performed studies to identify the P450 isoform(s) involved in the N-desethylation of CQ. In HLM incubated with CQ, only DCQ could be detected. Apparent K m and V max values (mean ؎ S.D.) for metabolite formation were 444 ؎ 121 M and 617 ؎ 128 pmol/min/mg protein, respectively. In microsomes from a panel of 16 human livers phenotyped for 10 different P450 isoforms, DCQ formation was highly correlated with testosterone 6␤-hydroxylation (r ‫؍‬ 0.80; p < 0.001), a CYP3A-mediated reaction, and CYP2C8-mediated paclitaxel ␣-hydroxylation (r ‫؍‬ 0.82; p < 0.001). CQ N-desethylation was diminished when coincubated with quercetin (20-40% inhibition), ketoconazole, or troleandomycin (20-30% inhibition) and was strongly inhibited (80% inhibition) by a combination of ketoconazole and quercetin, which further corroborates the contribution of CYP2C8 and CYP3As. Of 10 cDNAexpressed human P450s examined, only CYP1A1, CYP2D6, CYP3A4, and CYP2C8 produced DCQ. CYP2C8 and CYP3A4 constituted low-affinity/high-capacity systems, whereas CYP2D6 was associated with higher affinity but a significantly lower capacity. This property may explain the ability of CQ to inhibit CYP2D6-mediated metabolism in vitro and in vivo. At therapeutically relevant concentrations (ϳ100 M CQ in the liver), CYP2C8, CYP3A4, and, to a much lesser extent, CYP2D6 are expected to account for most of the CQ N-desethylation.

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Section: Chloroquine N-desethylation By Cyp2c8 Cyp3a4 and Cyp2d6supporting

confidence: 87%

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confidence: 99%

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IN VITRO METABOLISM OF CHLOROQUINE: IDENTIFICATION OF CYP2C8, CYP3A4, AND CYP2D6 AS THE MAIN ISOFORMS CATALYZINGN-DESETHYLCHLOROQUINE FORMATION

Projean

Baune²,

Farinotti³

et al. 2003

Drug Metab Dispos

164

117

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“…Chloroquine pharmacokinetics in patients with rheumatoid disease are reported to be similar to those in healthy volunteers (Augustijns et al 1992;Frisk-Holmberg et al 1983). The correlation between dosage and steady-state chloroquine concentration is reported to be very poor, reflecting the wide interpatient variation in pharmacokinetic parameters (Augustijns et al 1992;Frisk-Holmberg et al 1979;Laaksonen et al 1975).…”

Section: Disposition In Patients With Rheumatic Diseasesmentioning

confidence: 85%

Clinical Pharmacokinetics of Slow-Acting Antirheumatic Drugs

Tett

1993

Clinical Pharmacokinetics

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The pharmacokinetics of the slow acting antirheumatic drugs (SAARDs), hydroxychloroquine, chloroquine, penicillamine, the gold complexes and sulphasalazine, in humans have been studied. For all these drugs, both in controlled clinical trials and in empirical observations from rheumatological practice, delays of several months are reported before full clinical effects are achieved. Variability in response is also characteristic of these agents. Pharmacokinetic factors may partially explain these clinical observations. Delays in the achievement of steady-state concentrations or of concentrations likely to have a therapeutic benefit may occur because of slow drug accumulation. Variable concentrations may arise after standard administered doses because of interindividual pharmacokinetic variability. These factors are likely to contribute to the delay in response and the variable response, respectively. Pharmacokinetics of the antimalarials, hydroxychloroquine and chloroquine, are characterised by extensive tissue sequestration with reported volumes of distribution in the thousands of litres. Both drugs have reported elimination half-lives of greater than 1 month. A 2- to 3-fold range occurs in the fraction of an oral dose absorbed from a tablet formulation. Variable interindividual clearance is also reported. Hydroxychloroquine and chloroquine are administered as racemates. Enantioselective disposition of both compounds occurs, again with notable interindividual variability. Sulphasalazine is split in the large intestine into sulphapyridine, proposed to be the active compound in rheumatoid arthritis, and mesalazine (5-aminosalicylic acid). Sulphapyridine is metabolised partly by acetylation, the rate of which is under genetic control. A wide range of sulphapyridine steady-state concentrations are reported after standard doses of sulphasalazine. The gold complexes are administered either intramuscularly or in an oral form (auranofin). Gold is widely distributed in the body. Very long terminal elimination half-lives and slow accumulation rates are reported. Penicillamine is administered orally. Its bioavailability is variable and may decrease by as much as 70% in the presence of food, antacids and iron salts. Penicillamine forms disulphide bonds with many proteins in the blood and tissues, creating potential slow release reservoirs of the drug. Like the other SAARDs, gold complexes and penicillamine are found in a wide range of blood concentrations after administration in standard doses to different individuals. More research must be conducted into the concentration-effect relationships of the SAARDs before the pharmacokinetic characteristics of these drugs can be used effectively to optimise patient therapy.

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“…[42, 43) Distribution and redistribution processes (from the various body compartments back to the intravascular space) rather than slow drug elimination, are the predominant factors governing chloroquine blood concentrations for months following its single dose administration,l20,44) Indeed, despite its long halflife, ranging from 20 to 60 days, chloroquine has a relatively high total clearance, approximating 0.10 Lih/kg from whole blood data and 0.7 to 1 L/h/kg from plasma data.l 8 ,20,21,42) In patients treated for long term arthritis, [45,46) or following multiple weekly doses for malaria prophylaxis, [22) the total plasma clearance of chloroquine was estimated at 0.35 to 1 Lih/kg.…”

Section: Eliminationmentioning

confidence: 98%

Clinical Pharmacokinetics and Metabolism of Chloroquine

Ducharme

Farinotti

1996

Clinical Pharmacokinetics

272

233

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This paper presents the current state of knowledge on chloroquine disposition, with special emphasis on stereoselectivity and microsomal metabolism. In addition, the impact of the patient's physiopathological status and ethnic origin on chloroquine pharmacokinetics is discussed. In humans, chloroquine concentrations decline multiexponentially. The drug is extensively distributed, with a volume of distribution of 200 to 800 L/kg when calculated from plasma concentrations and 200 L/kg when estimated from whole blood data (concentrations being 5 to 10 times higher). Chloroquine is 60% bound to plasma proteins and equally cleared by the kidney and liver. Following administration chloroquine is rapidly dealkylated via cytochrome P450 enzymes (CYP) into the pharmacologically active desethylchloroquine and bisdesethylchloroquine. Desethylchloroquine and bisdesethylchloroquine concentrations reach 40 and 10% of chloroquine concentrations, respectively; both chloroquine and desethylchloroquine concentrations decline slowly, with elimination half-lives of 20 to 60 days. Both parent drug and metabolite can be detected in urine months after a single dose. In vitro and in vivo, chloroquine and desethylchloroquine competitively inhibit CYP2D1/6-mediated reactions. Limited in vitro studies and preliminary data from clinical experiments and observations point to CYP3A and CYP2D6 as the 2 major isoforms affected by or involved in chloroquine metabolism. In vitro efficacy studies did not detect any difference in potency between chloroquine enantiomers but, in vivo in rats, S(+)-chloroquine had a lower dose that elicited 50% of the maximal effect (ED950) than that of R(-)-chloroquine. Stereoselectivity in chloroquine body disposition could be responsible for this discrepancy. Chloroquine binding to plasma proteins is stereoselective, favouring S(+)-chloroquine (67% vs 35% for the R-enantiomer). Hence, unbound plasma concentrations are higher for R(-)-chloroquine. Following separate administration of the individual enantiomers, R(-)-chloroquine reached higher and more sustained blood concentrations. The shorter half-life of S(+)-chloroquine appears secondary to its faster clearance. Blood concentrations of the S(+)-forms of desethylchloroquine always exceeded those of the R(-)-forms, pointing to a preferential metabolism of S(+)-chloroquine.

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Steady state disposition of chloroquine in patients with rheumatoid disease

Cited by 13 publications

References 3 publications

IN VITRO METABOLISM OF CHLOROQUINE: IDENTIFICATION OF CYP2C8, CYP3A4, AND CYP2D6 AS THE MAIN ISOFORMS CATALYZINGN-DESETHYLCHLOROQUINE FORMATION

IN VITRO METABOLISM OF CHLOROQUINE: IDENTIFICATION OF CYP2C8, CYP3A4, AND CYP2D6 AS THE MAIN ISOFORMS CATALYZINGN-DESETHYLCHLOROQUINE FORMATION

Clinical Pharmacokinetics of Slow-Acting Antirheumatic Drugs

Clinical Pharmacokinetics and Metabolism of Chloroquine

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