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.

No abstract

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.

1 Little is known about the comparative plasma protein binding of the antimalarial agents quinine (QN) and its isomer quinidine (QD). We have examined the in vitro binding of QN and QD to albumin, a,-acid glycoprotein, normal human plasma, and maternal and foetal umbilical cord plasma. 2 QN was more avidly bound than QD, and binding of both drugs was substantially higher to a,-acid glycoprotein than to albumin, indicating that ot,-acid glycoprotein is the more important binding protein.3 Protein and drug concentration dependent binding was evident for both QN and QD. The unbound fraction of both drugs fell with increasing albumin (10 to 60 g 1-1) and a,r-acid glycoprotein (0.5 to 2.0 g 1-1) concentration, and there was a marked increase in unbound fraction of QN (6 to 19%) and QD (13 to 36%) in human plasma when drug concentrations were increased over the antimalarial therapeutic range (0.5 to 10 mg 1-1). 4 In human volunteer plasma, the unbound fractions of QN and QD were 7.5 ± 2.2% and 12.3 ± 2.3% respectively, whilst the unbound fractions for both drugs were significantly higher in maternal plasma (QN = 13.0 ± 5.4%, QD= 18.3 ± 2.5%) and significantly higher still in foetal umbilical cord plasma (QN = 25.7 10%, QD = 35 ± 5.3%).