Kinetics of the distribution and elimination of chloroquine in the rat

• 1.1. The distribution of chloroquine was studied in the tissues and blood of rat.
• 2.2. The time to peak concentration and the maximum concentration varied in various tissues and were higher than for plasma and red blood cells.
• 3.3. The tissue to plasma concentration ratio increased with time up to 144th hr for some tissues while this ratio was still increasing at the 168th hr for other tissues.
• 4.4. The values of β estimated for the tissues were lower than those for plasma or red blood cells. The values differed from one another for the tissues but were similar for plasma and red blood cells.

     

Plasma chloroquine and desethylchloroquine concentrations in children during and after chloroquine treatment for malaria.

Twelve children with acute falciparum malaria were treated with 25 mg/kg chloroquine orally in three divided doses at 24 h intervals. Concentrations of chloroquine and its metabolite, desethylchloroquine, were measured in plasma from the beginning of treatment for up to 7 days using a high pressure liquid chromatography (h.p.l.c.) technique. Chloroquine was detectable in plasma within 30 min of giving the drug. Peak level was reached in 1-8 h after the first dose of 10 mg/kg and the peak concentrations ranged between 65 and 263 ng/ml. Chloroquine concentration declined slowly in plasma after stopping drug administration so that the concentration at the seventh day was 37.5% of the concentration on the third day. The apparent half-life was 3-4 days. Desethylchloroquine was detectable in plasma within 30 min of giving chloroquine and peak levels were reached in 2-12 h. Peak concentration after the first dose of chloroquine ranged between 9 and 62 ng/ml. Desethylchloroquine was also slowly cleared from plasma and mean concentration at the end of 7 days was 49% of the mean concentration at the end of 3 days.     

Synergistic interaction of a chloroquine metabolite with chloroquine against drug-resistant malaria parasites

We have previously shown that structural modification of chlorpromazine to introduce a basic side chain converts this chloroquine (CQ) resistance-reversing agent into a compound that has activity against Plasmodium falciparum in vitro. In an effort to further dissect the structural features that determine quinoline antimalarial activity and drug resistance-reversing activity, we have studied a series of aminoquinolines that are structurally related to CQ. We have analysed their haematin-binding activities, their antimalarial activities and their abilities to synergise the effect of CQ against drug-resistant P. falciparum. We found that a number of the aminoquinolines were able to interact with haematin but showed no or very weak antiparasitic activity. Interestingly, 4-amino-7-chloroquinoline, which is the CQ nucleus without the basic side chain, was able to act as a resistance-reversing agent. These studies point to structural features that may determine the resistance-modulating potential of weakly basic amphipaths. Interestingly, 4-amino-7-chloroquinoline is a metabolic breakdown product of CQ and may contribute to CQ activity against resistant parasites in vivo.     

The regional uptake of chloroquine in the rat brain.

The uptake of ip administered chloroquine diphosphate, 14 mg/ml/kg, into dissected regions of the rat brain with and without pyrogen pretreatment was investigated. A consistent pattern of uptake, not significantly altered by pyrogen pretreatment, was found. The highest concentration of chloroquine 1 hr after administration was found in the hypothalamus (1.278±0.114 μg/g; Mean ± SE), whereas the cortex (0.147±0.006 μg/g) had the lowest concentration. The corpus striatum (0.62±0.029 μg/g) had a smaller uptake than the hippocampus (0.693±0.011 μg/g), the cerebellum (0.676±0.055 μg/g), and the midbrain (0.644±0.053 μg/g). The difference of the uptake pattern from known catecholamine distribution in the rat brain leads to the conclusion that whereas no specific affinity of chloroquine for the catecholamine-rich regions have been proven, other unknown factors ensure a consistent pattern of chloroquine uptake. The implications of these findings in relation to the transient extrapyramidal disorders associated with the 4-aminoquinolines in some malarial patients, and the aberrant melanin pigmentation associated with the chronic use of chloroquine for some autoimmune diseases, are discussed.     

Comparative efficacy of chloroquine and cotrimoxazole in the treatment of acute uncomplicated falciparum malaria in Nigerian children

OBJECTIVES: To evaluate the efficacy of two dosing regimens of cotrimoxazole in the treatment of falciparum malaria and compare the efficacy with that of chloroquine, the first-line antimalaria drug in the area of study. DESIGN: A prospective cross sectional study. SETTINGS: Department of Clinical Pharmacology, University College Hospital, Ibadan, Nigeria. SUBJECTS: Ninety eight children with acute symptomatic uncomplicated falciparum malaria. MAIN OUTCOME MEASURES: Fever and other symptoms clearance times, parasite clearance times and the cure rates for chloroquine, three day and five day cotrimoxazole. RESULTS: Ninety eight children with acute symptomatic uncomplicated falciparum malaria were randomised to receive three doses of oral chloroquine and two regimens of cotrimoxazole. Pre-treatment clinical and parasitological parameters were similar in the three treatment groups. The fever and other symptoms clearance times were comparable in all the treatment groups: 1.83 +/- 1.3, 1.9 +/- 1.0 and 2.4 +/- 1.3 days for chloroquine, three day cotrimoxazole and five day cotrimoxazole, respectively p = 0.24. Parasite clearance times for the three treatment groups were also similar; 3.0 +/- 1.0, 3.1 +/- 0.7, and 3.0 +/- 1.0 days respectively for chloroquine, three day- and five day- cotrimoxazole; p = 0.96. The cure rates for chloroquine, three day and five day cotrimoxazole were 74.2%, 88.2% and 84.8%, respectively (x2 = 2.40, p = 0.30). The three treatment regimens were well tolerated. CONCLUSION: These results indicate that cotrimoxazole is as effective as chloroquine in treatment of acute symptomatic uncomplicated falciparum malaria in children resident in an endemic area of southwest Nigeria. It is an added advantage when malaria coexists with respiratory tract infections for which cotrimoxazole is the recommended drug.     

The pharmacokinetics of chloroquine in healthy Thai subjects and patients with Plasmodium vivax malaria.

The pharmacokinetics of chloroquine (CQ) and desethylchloroquine (DECQ) were studied in seven male Thai patients with P. vivax malaria and seven healthy male Thais, after the standard oral dosage regimen of CQ (a total dose of 1500 mg given over 3 days). All patients showed a rapid initial response to the treatment with median (range) values of fever and parasite clearance times of 13.7 (2-47) and 58 (33-38) h, respectively. In the patients, the median range Cmax value was significantly higher (1547 (996-2446) vs 838 (656-1587) ng ml-1), and AUC(0,28d) was greater (281 (250-515) vs 122 (103-182) micrograms ml-1 h). In addition, the median (AUC(0,28d) of DECQ was significantly greater (170 (72-265) vs 77 (49-140) micrograms ml-1 h). The AUC(0,28d) ratio of DECQ to CQ in patients was significantly higher than that in healthy subjects (0.67 (0.43-0.90) vs 0.51 (0.29-0.61)).     

Population pharmacokinetics of chloroquine and sulfadoxine and treatment response in children with malaria: suggestions for an improved dose regimen

AIMS

To describe the pharmacokinetics of chloroquine (CQ) and sulfadoxine (SDx), and to identify predictors of treatment response in children with malaria given the CQ + SDx and pyrimethamine (PYR) combination.

METHODS

Eighty-six Ugandan children with uncomplicated falciparum malaria, 6 months to 5 years old, were randomly treated with prepacked fixed-dose CQ + SDx/PYR. The youngest children (<24 months) received half strength and the older (>24 months) full strength treatment. The reported day 14 failure rates were 48% and 18%, respectively. Capillary blood (100 μl) applied on to filter paper was collected on eight occasions during 28 days of follow up. Concentrations of CQ and SDx were determined. A population approach was used for the pharmacokinetic analysis.

RESULTS

A two-compartment model adequately described the data for both CQ and SDx. For CQ, the typical apparent clearance (CL/F) and volume of distribution (V_C/F) values were estimated to be 2.84 l h⁻¹ and 230 l. The typical CL/F for SDx was 0.023 l h⁻¹, while the factor relating its V_C/F to normalized body weight was 1.6 l kg⁻¹. Post hoc parameter estimates for both drugs showed lower maximum concentrations (C_max) and concentration-time curve areas (AUC(0,336 h)) in younger children. The AUC(0,336 h) for SDx and CQ were independently significant factors for prediction of cure. Simulations suggest that giving the higher dose to the youngest children would result in higher CQ and SDx concentrations and improved outcome.

CONCLUSIONS

The study results suggest that full-strength combination to all children would improve the cure rate.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Both chloroquine (CQ) and sulfadoxine/ pyrimethamine (SDx/PYR) remain important drugs in the control of malaria.
• The available data on CQ, SDx and PYR are summary pharmacokinetic parameters based on classical/traditional methods, mostly in adults.
• No study has described the population pharmacokinetics of a fixed-dose CQ + SDx/PYR combination in children with falciparum malaria.

WHAT THIS STUDY ADDS

• This study presents population pharmacokinetic data on CQ and SDx in children with uncomplicated falciparum malaria.
• The study demonstrates that in age-based fixed-dose regimens with CQ and SDx, drug exposures and outcomes may be correctly predicted, although correlation with body weight is poor.
• The study proposes dose modification to improve response with the CQ + SDx/PYR combination.

     

Kinetics of paraquat elimination in the dog

The elimination and distribution kinetics of paraquat and the effect of paraquat-induced renal damage on these parameters have been studied in the dog. After intravenous administration, low doses (30–50 μg/kg) of paraquat were rapidly excreted in the urine at a clearance rate in excess of glomerular filtration rate, indicating that paraquat was eliminated by active secretion. This secretion could be inhibited by competition with N′-methylnicotinamide, a quaternary ammonium compound. Large doses (20 mg/kg) of paraquat induced renal failure, the extent of renal function impairment depending on the dose. The plasma concentration-time curve showed a triexponential decline, so that the elimination of paraquat could be described by a three-compartment open model. Simulation of paraquat levels in the peripheral compartments indicated that with early renal failure, fivefold higher levels would be achieved in the slow uptake compartment than under conditions of normal renal function. Since the energy-dependent accumulation of paraquat by the lung is a slow process, it was assumed that the slow uptake compartment included the lung. The implications of this are discussed in relation to the rational treatment of paraquat poisoning in man.     

Therapeutic drugs for targeting chloroquine resistance in malaria

While the post-genomic era could lead into new targets for antimalarial drug development, herein few successful targets including medicinals involved in those processes are presented. Further, contribution of bioinorganic chemistry has also started to make its impact in the field of pharmaceuticals. Therefore, metal chelators, selected organometallics, and metalloantimalarials that would offer potential therapeutic drugs are also discussed. Finally, a brief summary on chloroquine-resistance mechanism(s) has been included.     

A study of chloroquine and desethylchloroquine plasma levels in patients infected with sensitive and resistant malaria parasites.

This study was carried out on 63 patients in the town of Gadaref in eastern Sudan; each patient was given the standard therapeutic dose of chloroquine (CQ). Plasma levels of chloroquine and its major metabolite desethylchloroquine (DCQ) were measured by means of a high-performance liquid chromatographic method (HPLC) in patients infected with sensitive (sensitive group) and resistant (resistant groups) strains of Plasmodium falciparum. The ratios of chloroquine to desethylchloroquine (CQ/DCQ) in different groups were calculated and the results obtained were compared and correlated with the degree of parasitaemia. The statistical analysis of the results showed that the plasma content of CQ and the CQ/DCQ ratio in the majority of the patients fall within the normal mode of distribution. A small group of patients showed a deviation from the normal mode by having a rather high CQ plasma level and a high ratio of CQ/DCQ. The mean plasma levels of CQ and the CQ/DCQ ratio in the sensitive group was found to be higher than that in the resistant groups. However, these differences were found to be not significant. Correlation tests showed that the levels of CQ and the CQ/DCQ ratios increase with the increase of the degree of parasitaemia in the sensitive group but decrease with the increase of parasitaemia in resistant groups.     

Kinetics of absorption and elimination of pralidoxime chloride in dogs.

The kinetics of the absorption and elimination of pralidoxime chloride were investigated in the dog. Similar apparent elimination rate constants were obtained after intravenous, intramuscular, and oral administration. Although oral absorption occurred slowly, intramuscular absorption proceeded rapidly. With in situ techniques, it was found that no absorption occurred from the isolated stomach and duodenum but that absorption did take place from the jejunum and ileum.     

Kinetics of diphenylhydantoin elimination in rats

Concentrations of diphenylhydantoin (DPH) in the blood of male Sprague-Dawley rats after intravenous injection of 10 and 40 mg/kg ¹⁴C-DPHwere determined over a sufficiently wide range to permit comparison of rates of decline at the same absolute and relative concentrations. This comparison leads to the conclusion that the elimination of DPH in the rat cannot be described by first-order or simple Michaelis-Menten kinetics but that it is qualitatively consistent with product inhibition of DPH metabolism.Supported in part by grant GM 19568 from the National Institutes of Health.On leave from the School of Pharmacy, University of Sydney, Sydney, Australia.     

A comparative study of the schizontocidal efficacy and safety of artemether versus chloroquine in uncomplicated malaria.

Forty-seven patients with uncomplicated falciparum malaria were randomly assigned to receive either artemether (n = 24), 9.6 mg/kg body weight intramuscularly over five days or chloroquine (n = 23), 25 mg/kg body weight orally. Patients were kept in hospital for seven days followed by review on days 14, 21 and 28. Five patients on chloroquine were withdrawn before day seven due to treatment failure. Of the remaining patients, parasite clearance time was 33.0 +/- 13.6 hours for the artemether group and 63.3 +/- 14.7 hours for patients on chloroquine (p < 0.001). No significant difference was recorded in fever clearance time between the two groups of patients. Recrudescence rate for patients on artemether was 14.3 pc compared to 57.1 pc for the chloroquine group (p < 0.05). No major adverse events were recorded for either treatment group although five patients on artemether had a transient spike of temperature after clearance of parasitaemia. In conclusion, our study has shown that no major adverse events were experienced by patients on artemether and the rate of parasite clearance for the artemether group was superior to that of patients on chloroquine.     

Linear and nonlinear kinetics of drug elimination I. Kinetics on the basis of a single capacity-limited pathway of elimination with or without simultaneous supply-limited elimination

The pharmacokinetic behavior of foreign substances that are completely or partially eliminated via metabolism by saturable enzyme systems is analyzed. General integrated equations are derived which describe the time course of the plasma concentration under the assumption of a saturable enzyme system according to Michaelis-Menten kinetics in combination with normal firstorder elimination processes. A procedure for the estimation of initial values of the elementary kinetic parameters on the basis of the models is outlined. These initial values have been used in a nonlinear curvefitting program in order to obtain reliable kinetic and enzyme parameters from the plasma curves. With these methods, kinetic and apparent enzyme parameters are calculated for ethanol, salicylic acid, 4-hydroxybutyric acid, and phenytoin. Financial support was provided by the Prevention Fund of the Dutch Ministry of Health and by the Dutch Foundation of Medical Research (Fungo-TNO).     

Halofantrine pharmacokinetics in Kenyan children with non-severe and severe malaria.

1. Kenyan children with uncomplicated malaria given oral halofantrine (HF; non-micronised suspension; 8 mg base kg-1 body weight 6 hourly for three doses) showed wide variation in the disposition of HF and desbutylhalofantrine (HFm). 2. Eight Kenyan children with severe (prostrate) falciparum malaria who were receiving intravenous quinine, were given the same HF regimen by nasogastric tube. One patient had undetectable HF and two had undetectable HFm at all times after drug administration. 3. The mean AUC(0,24 h) of HF in prostrate children was half (7.54 compared with 13.10 micrograms ml-1 h) (P = 0.06), and that for HFm one-third (0.84 compared with 2.51 micrograms ml-1 h) (P < 0.05) of the value in children with uncomplicated malaria. 4. Oral HF may be appropriate for some cases of uncomplicated falciparum malaria in Africa, but in patients with severe malaria, the bioavailability of HF and HFm may be inadequate.     

Mefloquine pharmacokinetics and resistance in children with acute falciparum malaria.

The pharmacokinetic properties of mefloquine hydrochloride (15 mg base kg -1) were studied in 12 Karen children (five girls, seven boys) aged between 5 and 10 years presenting with uncomplicated falciparum malaria. The drug was well tolerated. Mean (s.d.) peak blood drug concentrations of 2031 (831) ng ml-1 were reached in a median of 8 (range 6-24) h. Mean (s.d.) estimates for oral clearance and mean residence time were 0.52 (0.27) ml min -1 kg -1 and 15.3 (4.7) days, respectively. These values are similar to those reported previously in adults. In one child parasitaemia failed to clear despite whole blood mefloquine concentrations which peaked at 1744 ng ml -1; parasitaemia rose and fever recurred when blood drug concentrations had fallen to 442 ng ml -1. The prevalence of highly mefloquine resistant parasites such as this can be expected to increase under drug pressure in this area.