Effects of an NADPH-generating system on primaquine degradation by hamster liver fractions.

1. Primaquine (PQ) often causes severe anaemia in individuals with glucose 6-phosphate dehydrogenase (G6PD) deficient erythrocytes, and metabolites have been implicated as the toxic substance. These studies present data identifying additional metabolites of PQ. 2. Two metabolites of primaquine (PQ) previously identified in human studies, namely, 6-methoxy-8-aminoquinoline (MAQ) and 8-(3-carboxy-1-methylpropylamino)-6-methoxyquinoline (PQC) were also formed on incubation of PQ with hamster liver fractions for up to 24 h without an NADPH-generating system. 3. The alcohol (PQAOH) and lactam (PQLT) derivatives of PQ were also formed on incubation with hamster liver fraction used in these studies. 4. The microsomal metabolism of PQ was decreased in presence of an NADPH-generating system, but not by SKF-525A or glutathione (GSH) indicating that the oxidative reactions were probably not due to the cytochrome P-450 system or free radical mechanisms.

Glucose effect on drug action, metabolism, and pharmacokinetic parameters in mice.

The glucose effect on hepatic drug metabolism (decreased) of barbiturates was maximum after 2 days of increased glucose intake as indicated by increased barbiturate sleep time in mice. However, this effect was not observed after 5 days of glucose treatment, and barbiturate sleep time was similar to the control after 6 days of treatment. Serum glucose and liver glycogen were, in general, not significantly different from control, even after chronic glucose intake, indicating that neither hypoglycemia nor alteration of liver glycogen levels were required for the glucose effect on drug action. However, in contrast to the decreased metabolism of barbiturate, there was increased metabolism of glucose in the glucose-treated animals. Brain levels of barbiturate in 48 hours glucose-treated mice were higher and declined at approximately half the rate of controls (Ke(G) 0.009 vs Ke(C) 0.015). A similar trend in barbiturate blood concentration indicated decreased metabolism of the barbiturate and/or decreased clearance of drug and metabolites. The glucose treatment altered the pentobarbital dose response curve, but there appeared to be no alteration of the sensitivity to insulin; exogenase insulin still produced significant hypoglycemia and prolonged barbiturate S.T. after 7 days of glucose treatment. Other factors may be involved in the glucose effect; increased permeability of the brain to barbiturate, decreased permeability to outflow so that brain concentrations remain higher for a long period of time.