Absolute bioavailability of quinine formulations in Nigeria.

This study compared the absolute bioavailability of quinine sulphate as capsule and as tablet against the intravenous (i.v.) infusion of the drug in twelve male volunteers. Six of the volunteers received intravenous infusion over 4 h as well as the capsule formulation of the drug in a cross-over manner, while the other six received the tablet formulation. Blood samples were taken at predetermined time intervals and plasma analysed for quinine (QN) using reversed-phase HPLC method. QN was rapidly absorbed after the two oral formulations with average t(max) of 2.67 h for both capsule and tablet. The mean elimination half-life of QN from the i.v. and oral dosage forms varied between 10 and 13.5 hr and were not statistically different (P > 0.05). On the contrary, the maximum plasma concentration (C(max)) and area under the curve (AUC) from capsule were comparable to those from i.v. (P > 0.05), while these values were markedly higher than values from tablet formulation (P < 0.05). The therapeutic QN plasma levels were not achieved with the tablet formulation. The absolute bioavailability (F) were 73% (C.l., 53.3 - 92.4%) and 39 % (C.I., 21.7 - 56.6%) for the capsule and tablet respectively and the difference was significant (P < 0.05). The subtherapeutic levels obtained from the tablet form used in this study may cause treatment failure during malaria and caution should be taken when predictions are made from results obtained from different formulations of QN.

Polymorphic oxidative metabolism of proguanil in a Nigerian population.

OBJECTIVE: The genetic polymorphic metabolic oxidation of proguanil was investigated in 126 healthy, unrelated Nigerian subjects as an indication of the phenotypic status of CYP2C19 in Nigerians. METHODS: The proguanil oxidation capacity was determined using the 8-h urinary metabolic ratio of the parent drug and its metabolite (cycloguanil) after a single oral dose of 200 mg proguanil. RESULTS: The frequency distribution of the proguanil metabolic ratio ranged from 0.01 to 39.64 with a median of 1.38 in the 126 Nigerians. On the basis of the antimode value of 10 for the proguanil/cycloguanil ratio, the prevalence of poor metabolisers in this Nigerian population was estimated to be 4.8% (6 of 126), which is very similar to that of S-mephenytoin (4.3%) found in a previous study in Nigerians. The data also demonstrated enormous inter-individual differences in the urinary proguanil/cycloguanil ratios with poor metabolisers excreting, on average, only about 8% of the quantity of cycloguanil excreted by extensive metabolisers. CONCLUSION: The incidence of phenotypically poor metabolisers of proguanil in this Nigerian population is similar to those reported for Caucasian and other African populations but is much lower than those reported for Orientals. The study further supports previous studies that proguanil can be used as an alternative probe to phenotype for CYP2C19 activity.

Pharmacokinetic aspects of chloroquine-induced pruritus: influence of dose and evidence for varied extent of metabolism of the drug.

The significance of a pharmacokinetics basis in chloroquine (CQ)-induced pruritus was investigated by determining the disposition of the drug in two groups of volunteers; pruritus positive and pruritus negative. Single oral dose of 600 mg CQ was administered to each of 36 volunteers, 18 for each of the two groups. After a washout period of 9 months, 150 mg single oral dose of the drug was given to 12 of the same volunteers, six each from the two groups. Blood and urine samples were collected at predetermined times following administration of each dose. Concentrations of CQ and its major metabolite, desethylchloroquine (CQM), were measured in plasma and urine using an established HPLC method. Results showed that the ratio, AUC (CQ)/AUC (CQM), as well as AUC(0-48 h) and 24-h urinary CQ excretion were all significantly higher (P<0.05) in pruritus-positive compared to pruritus-negative volunteers, following administration of the 600-mg CQ dose. Also, urinary drug-metabolite ratios monitored over 0-48 h postdose were markedly higher in the pruritus positive group. However, after administration of the 150-mg dose, 24-h urinary CQ collection and urinary drug-metabolite ratios were highly comparable between the two groups (P>0.1). This study indicates that there might be a decreased metabolism of CQ in subjects susceptible to CQ-induced pruritus following ingestion of a therapeutic dose. It also suggests that the extent of metabolism of CQ in this group may be influenced by the dose of the drug. Comparatively higher CQ levels in pruritus susceptible subjects may possibly be responsible for the pruritus experienced by such individuals when given therapeutic regimen.

Pharmacokinetics of quinine in African patients with acute falciparum malaria.

The pharmacokinetics of quinine were studied in six Nigerian patients during acute uncomplicated falciparum malaria and convalescent periods. An oral dose of 10 mg/kg quinine dihydrochloride administered 8-hourly for 7 days gave parasite and fever clearance times of 36.0 +/- 16.6 h and 18.0 +/- 6.4 h, respectively. From the individual quinine plasma profiles the mean plasma concentration of quinine at the time of parasite clearance was estimated as 4.5 +/- 1.1 micrograms/ml. Plasma quinine levels during malaria rose rapidly reaching a peak around the second and third days and declining thereafter as patients improved clinically. In acute malaria plasma quinine levels were more than two-fold higher than in convalescence; the mean AUC(0-12) in malaria was 37.9 +/- 14.7 micrograms.h/ml compared to 17.9 +/- 8.5 micrograms.h/ml in convalescence. The apparent oral clearance (CL/F) and volume of distribution (Vd/F) during the acute phase of the malaria (1.9 +/- 0.7 ml/min/kg and 1.8 +/- 0.9 l/kg, respectively) were significantly lower than in convalescence (4.5 +/- 2.1 ml/min/kg and 4.2 +/- 3.2 l/kg). The present data suggest that malaria parasites in African patients are still very sensitive to quinine and that the current dosage of quinine is effective for the treatment of acute falciparum malaria in African patients without augmenting therapy with any other drug such as tetracycline or sulphadoxine-pyrimethamine. It also confirms that malaria significantly alters the pharmacokinetics of quinine in humans.

Time-dependent variability of chloroquine secretion into human saliva.

Chloroquine has been reported to be secreted into human saliva. This is a report of a study designed to underscore the importance of the finding. It involved the administration of 600 mg chloroquine per oral to seven volunteers and 150 mg by intramuscular route to six others. Blood and simultaneous saliva samples were collected and analyzed for the drug by an HPLC method. The results showed that chloroquine reaches peak concentration at the same time in both plasma and saliva after oral administration of the drug. A good correlation was obtained between the AUC values derived from saliva and plasma level data. Saliva to plasma concentration ratios obtained after administration of the drug by both routes were high (mean > 11) and exhibited a time-dependent variability. These results suggest that an active process, among other mechanisms, may be involved in the transfer of chloroquine into human saliva. Caution should be exercised in the use of saliva for therapeutic monitoring of chloroquine.

Pharmacokinetics and bioavailability of drotaverine in humans.

The pharmacokinetics and bioavailability of drotaverine was studied in 10 healthy volunteers after administration of single 80 mg oral and intravenous doses of the HCl salt of the drug, in a crossover fashion. Plasma and urine samples were analyzed for the unchanged drug by HPLC. The pharmacokinetic parameters, such as elimination half-life, plasma clearance, renal clearance and apparent volume of distribution, were not influenced by the route of drug administration. The drug was mainly eliminated by non-renal routes since renal clearance accounted for only 0.31 +/- 0.13% of the total plasma clearance. The absolute bioavailability was variable and ranged from 24.5-91% with a mean of 58.2 +/- 18.2% (mean +/- SD). It is suggested that the high variation in the bioavailability of drotaverine HCl after oral administration may result in significant interindividual differences in therapeutic response.

Relationship between plasma and saliva quinine levels in humans.

The relationship between saliva and plasma levels of quinine was studied in four healthy volunteers. After a single oral dose of quinine sulfate (600 mg) to the volunteers, quinine was determined in both saliva and plasma simultaneously over a 48-h period by an ion pair reverse-phase high performance liquid chromatography method. The tmax (4.3 +/- 0.5 h) and elimination half-life (11.8 +/- 2.9 h) of quinine derived from saliva levels were comparable with those obtained from plasma levels (tmax = 2.8 +/- 0.2 h, t1/2 = 12.9 +/- 2.3 h). A significant correlation existed between the plasma and saliva concentrations of the drug (r = 0.93, n = 20, p < 0.001). The mean saliva/plasma quinine concentration ratio was 0.24 +/- 0.02. The results suggest that quinine is passively secreted into saliva and that saliva level determination may be useful as a noninvasive method in the evaluation of pharmacokinetic parameters and therapeutic drug monitoring of quinine.

Bioavailability of sulphate and dihydrochloride salts of quinine.

A comparative bioavailability of three formulations of quinine was performed in 6 healthy male adult Africans after intravenous infusion of 600mg quinine hydrochloride in 0.9% saline over 4 hours and after single oral doses of 600mg quinine sulphate capsule, 600mg quinine dihydrochloride plain tablet and 600mg quinine sulphate sugar coated tablet. The drugs were given according to a randomised cross-over design. The quinine sulphate coated tablet was found to contain no quinine. There was no statistical significant difference (P > 0.05) in the plasma Cmax, tmax, AUC and Ka values between the quinine sulphate capsule and quinine dihydrochloride plain tablet, although a considerable degree of inter- and intra-individual variability in the pharmacokinetic parameters was observed. The absolute bioavailability was 64.5 and 64.3% for the quinine sulphate capsule and the quinine dihydrochloride plain tablet respectively. The non-detection of quinine in the sugar coated tablet (obtained from Nigeria) confirms the presence of fake circulating antimalarial drugs in the country.

High-performance liquid chromatographic method for the determination of drotaverine in human plasma and urine.

A simple and sensitive HPLC method for the determination of drotaverine in human plasma and urine has been developed. Alkalinized plasma or urine was extracted with organic solvent and the basic components in the organic phase were back-extracted into 0.1 M HCl. An aliquot of the aqueous layer was injected onto the column and the eluent was monitored at 254 nm. Separation was performed on a C18-column with 0.02 M sodium dihydrogen phosphate-methanol (30:70, v/v) containing perchlorate ion at pH 3.2 as mobile phase. Drotaverine was well resolved from the plasma constituents and internal standard. An excellent linearity was observed between peak-height ratios and plasma concentrations and the intra- and inter-assay coefficients of variation were always < 10%. The lowest limit of detection (signal-to-noise ratio 3:1) was 6 ng/ml. The method is suitable for therapeutic monitoring and pharmacokinetic studies of drotaverine in humans as well as in animal models.

Column liquid chromatographic analysis of quinine in human plasma, saliva and urine.

A new simple, selective and reproducible high-performance liquid chromatographic method for the determination of quinine in plasma, saliva and urine is described. The ion-pair method was carried out on a reversed-phase C18 column, using perchlorate ion as the counter ion and ultraviolet detection at 254 nm. Quinine was well resolved from its major metabolite, 3-hydroxyquinine, and the internal standard, primaquine. The limit of detection was 10 ng/ml and the recovery was greater than 90% from the three biological fluids.

Lack of pharmacokinetic interaction between chloroquine and imipramine.

The pharmacokinetic interaction between chloroquine (CQ) and imipramine was investigated in six healthy volunteers who received 300 mg of CQ, 50 mg of imipramine, and combined doses of both drugs in a randomized, crossover design. Blood and urine samples were collected at predetermined time intervals and were analyzed for the drugs and their metabolites by high-performance liquid chromatography methods. The results revealed that the plasma concentrations of CQ and its pharmacokinetic parameters were not significantly altered when CQ was coadministered with imipramine (p > 0.1). The plasma concentration-time profiles and the disposition characteristics of imipramine also were not altered after coadministration with CQ. The results suggest that there appears to be no pharmacokinetic interaction between CQ and imipramine given as single oral doses.

An in-vitro study of chloroquine transport in the rat submaxillary gland.

The uptake and efflux of chloroquine by the rat submaxillary gland in-vitro were studied under various incubation conditions. Variations in the extracellular pH significantly affected both the uptake and efflux of the drug. Increasing chloroquine concentration significantly decreased the uptake. Uptake was also decreased significantly (P less than 0.05) when compared with control conditions (pH 7.40, 37.5 degrees C, O2 aeration, 6 x 10(-6) M chloroquine) by the following experimental variations: aeration of the incubation medium with N2 instead of O2; decrease of bath temperature from 37.5 to 4 degrees C; addition of metabolic inhibitors, cyanide (10(-3) M), iodoacetic acid (10(-3) M) and o-nitrophenol (10(-3) M). Cimetidine (10(-3) M), a known organic cationic inhibitor, had no significant effect on chloroquine uptake when compared with control values. These results show that the uptake of chloroquine by the rat submaxillary gland in-vitro is concentration-dependent and this is indicative of possible saturable binding sites for the drug in the gland. These results suggest that the transfer of chloroquine across the submaxillary gland may be mediated by an active transport process. On the other hand, it is possible that the apparent active transport process implicated in this study could be a consequence of chloroquine ion trapping in the acidic interior of lysosomes.

Excretion of proguanil in human saliva.

After a single oral administration of a 300 mg dose of proguanil to six volunteers, the presence of the drug in saliva was established by chromatographic and spectrophotometric methods. The tmax and elimination half-life of proguanil derived from salivary levels were 4.0 +/- 1.26 h and 15.1 +/- 1.8 h, respectively. These results are in agreement with values previously reported for the drug using plasma level data. The mean saliva: plasma proguanil concentration ratio was 0.41 +/- 0.17 and this was not time dependent. There was a correlation (r = 0.82) between the saliva and simultaneous plasma proguanil concentration. The results suggest that proguanil is passively secreted into saliva and that saliva levels may be useful in the determination of pharmacokinetic parameters and the therapeutic monitoring of the drug.

Excretion of chloroquine and desethylchloroquine in human milk.

The excretion of chloroquine and the major metabolite, desethylchloroquine, in breast milk was investigated in eleven lactating mothers following a single oral dose of chloroquine (600 mg base). The average milk to plasma concentration ratio at the 24th hour was 6.6 +/- 2.4 for chloroquine and 1.5 +/- 0.6 for desethylchloroquine in five of the volunteers. In five other volunteers the elimination half-life of chloroquine in milk was 8.8 +/- 4.7 days which was longer than that in saliva (3.9 +/- 1.0 days) from the same volunteers. The maximum daily dose of the drug that the infant can receive from breastfeeding was about 0.7% of the maternal start dose of the drug in malaria chemotherapy. It is, therefore, suggested that it is safe for mothers to breastfeed their infants when undergoing treatment for malaria with chloroquine.

Comparative bioavailability studies on some brands of ampicillin capsules.

The bioequivalence of two generics of Ampicillin capsules, hitherto untested, were assessed using Penbritin capsules, the innovator's brand, as the reference product. The bioavailability study was carried out in nine healthy volunteers given one capsule (250 mg) of ampicillin in a completely randomized cross-over design. Statistical analysis (ANOVA) of the results indicated that one of the products tested, designated ampicillin (X), was significantly different (p less than 0.05) in its bioavailability compared to Penbritin while the other product, ampicillin (Helm), was not.

Fat contents of meals and bioavailability of griseofulvin in man.

The bioavailability of griseofulvin was followed in twelve healthy volunteers by measuring the urinary excretion of the major metabolite 6-demethylgriseolfulvin, after each volunteer had ingested one 500 mg griseofulvin tablet under (1) fasting conditions, (2) immediately after a typical low-fat and (3) high-fat Nigerian meals. An increase of about 70 and 120% absorption occurred with the ingestion of the low-fat and high-fat meals respectively compared to the fasting state (P less than 0.01). The maximum excretion rates of the free metabolite (Vmax.) were also significantly increased (P less than 0.01) following consumption of low and high fat meals. Our results thus suggest that the higher the fat content of the meals the higher the enhancement of the bioavailability of griseofulvin in man.

Comparative bioavailability studies on brands of diazepam tablets.

The chemical and biological equivalence of two brands of diazepam tablets marketed in Nigeria were compared to that of Valium (Roche) tablets. The tablets used were Relanium (Polfa) and Tropium (Biode). Bioequivalence studies of the brands were carried out on nine healthy volunteers by monitoring the cumulative diazepam excreted as oxazepam (both free and conjugated) in urine over 48 h. The bioequivalence of Relanium was found not to be significantly different from that of Valium while that of Tropium was significantly different from that of Valium (P less than 0.05). The results of the investigation showed that the drug products were all chemical equivalents but not biological equivalents.