A method is described for the simultaneous determination of the carboxylic acid and N‐acetyl‐derivatives of primaquine, in plasma and urine. After oral administration of 45 mg primaquine, to five healthy volunteers, absorption was rapid, with peak primaquine levels of 153.3 +/‐ 23.5 ng/ml at 3 +/‐ 1 h, followed by an elimination half‐life of 7.1 +/‐ 1.6 h, systemic clearance of 21.1 +/‐ 7.1 l/h, volume of distribution of 205 +/‐ 371 and cumulative urinary excretion of 1.3 +/‐ 0.9% of the dose. Primaquine underwent rapid conversion to the carboxylic acid metabolite of primaquine, which achieved peak levels of 1427 +/‐ 307 ng/ml at 7 +/‐ 4 h. Levels of this metabolite were sustained in excess of 1000 ng/ml for the 24 h study period, and no carboxyprimaquine was recovered in urine. N‐acetyl primaquine was not detected in plasma or urine. Following [14C]‐primaquine administration to one subject, plasma radioactivity levels rapidly exceeded primaquine concentrations. Plasma radioactivity was accounted for mainly as carboxyprimaquine . Though 64% of the dose was recovered over 143 h, as [14C]‐radioactivity in urine, only 3.6% was due to primaquine. As neither carboxyprimaquine nor N‐ acetylprimaquine were detected in urine, the remaining radioactivity was due to unidentified metabolites.

1 Plasma concentrations of halofantrine (Hf) and its putative principal plasma metabolite desbutyl halofantrine (Hfm) have been measured in two separate studies after oral administration of the hydrochloride salt. 2 Six healthy male volunteers each received single oral doses of 250, 500 and 1000 mg administered after an overnight fast. A washout period of at least 6 weeks was allowed between each dose. A further 250 mg single oral dose was administered to the same six subjects in a fasting state and after a standardised fatty meal in a randomised study, again with a washout period of at least 6 weeks. 3 AUC and maximum plasma concentration (Cmax) for Hf increased in proportion to the dose from 250-500 mg. This increase was non-proportional when the dose was increased from 500 to 1000 mg. For Hfm, in the dose range 250-500 mg, AUC but not Cmax increased in proportion in the increase in dose size. The increase in these parameters was nonproportional when the dose was increased from 500 to 1000 mg. Time to reach peak concentrations for Hf and Hfm and the elimination half-life of Hf remained unchanged across the dosage range. 4 Following a fatty meal, Cmax for Hf was increased from 184 ± 115 ,ug 1-1 (fasting) to 1218 ± 464 ,ug 1-1 (fed). AUC for Hf was increased from 3.9 ± 2.6 mg l-1 h (fasting) to 11.3 ± 3.5 mg 1-1 h following a fatty meal. The AUC for Hfm was also increased from 8.8 ± 3.5 mg I-1 h (fasting) to 10.7 ± 3.2 mg 1-1 h (fed). 5 Hf was not detected in urine, and -0.01% of the dose was present as Hfm. 6 These data suggest that after oral administration of Hf hydrochloride, linear pharmacokinetics are observed in the single dose range of 250-500 mg. The apparent non-linearity above 500 mg may be a function of the poor solubility of Hf. 7 The relative systemic availability of Hf is increased significantly in the presence of food of high fat content. The mechanism responsible for this effect and its clinical consequences remain to be established.

1 A method is described for the simultaneous determination of amodiaquine (AQ) and desethylamodiaquine (AQm) in plasma, urine, whole blood and packed red cells. 2 After oral administration of AQ (600 mg) to seven healthy subjects, absorption of AQ was rapid, reaching peak concentrations in plasma, whole blood, and packed cells at 0.5 ± 0.03, 0.5 ± 0.1 and 0.5 ± 0.1 h respectively (mean ± s.e. mean). The apparent terminal half-life of AQ was 5.2 ± 1.7 h. AQ was detectable for no longer than 8 h. 3 AQ underwent rapid conversion to AQm, which reached peak concentrations in plasma, whole blood and packed cells at 3.4 ± 0.8, 2.3 ± 0.5 and 3.6 ± 1.1 h respectively. AQm was still detectable at the end of the sampling period (96 h) when the plasma concentration was 29 ± 8 ng ml-1. 4 The area under the plasma concentration vs time curve (AUC(0,oo)) for AQ was 154 + 38 ng ml-1 h; the corresponding value for AQm was 8037 ± 1383 ng ml -1 h. There were no significant differences in the values for AUC of AQ between plasma, whole blood, or packed cells. 5 The whole blood to plasma concentration ratio for AQm was 3.1 ± 0.2, and the AUC (0,24) for AQm in whole blood (6811 ± 752 ng ml-' h) was significantly greater than that in plasma (2304 ± 371 ng ml-' h), P < 0.001.6 The recovery of AQm from urine collected 0-24 h was 6.8 ± 0.8 mg (n = 6). In one subject urine was collected up to 5 months after dosing, and recoveries of AQ and AQm were 3.0 mg (0-1 month) and 57 mg (0,00) respectively. AQ and AQm were still detectable in urine 5 months after dosing.

1 The pharmacokinetics of primaquine have been examined in five healthy volunteers who received single oral doses of 15, 30 and 45 mg of the drug, on separate occasions. Each subject received an i.v. tracer dose of [14C]-primaquine (7.5 ,uCi), simultaneously with the 45 mg oral dose. 2 Absorption of primaquine was virtually complete with a mean absolute bioavailability of 0.96 ± 0.08. 3 Elimination half-life, oral clearance and apparent volume of distribution for both primaquine and the carboxylic acid metabolite were unaffected by either dose size, or route of administration. 4 The relationships between area under the curve and dose size were linear for both primaquine (r = 0.99, P -0.01) and its carboxylic acid metabolite (r = 0.99, P , 0.01). 5 The mean whole blood to plasma concentration ratios were determined for primaquine (0.81), and for the carboxylic acid metabolite of primaquine (0.84). 6 Primaquine is a low clearance compound (CL = 24.2 ± 7.4 1 h-1), is extensively distributed into body tissues (V = 242.9 ± 69.51) and is not subject to extensive first pass metabolism.

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