The effects of diltiazem on hepatic drug metabolizing enzymes in man using antipyrine, trimethadione and debrisoquine as model substrates.

Six healthy male subjects were given single oral doses of antipyrine (7 mg kg-1), trimethadione (4 mg kg-1) and debrisoquine (10 mg) before and during diltiazem treatment (30 mg three times daily orally for 8 days). Antipyrine clearance decreased from 33.7 +/- 9.1 to 22.5 +/- 4.9 ml min-1 (P less than 0.05, mean +/- s.e. mean) after diltiazem treatment without any significant change in apparent volume of distribution (0.59 +/- 0.06 to 0.60 +/- 0.04 1 kg-1), resulting in an increase in antipyrine elimination half-life from 13.4 +/- 4.8 to 19.7 +/- 3.2 h (P less than 0.05). The formation clearance of antipyrine to 4-hydroxyantipyrine was decreased significantly from 10.8 +/- 2.7 to 6.6 +/- 2.7 ml min-1 (P less than 0.05), while that to 3-hydroxymethylantipyrine and norantipyrine was not altered by diltiazem. The metabolic ratio of debrisoquine (urinary excretion of debrisoquine/4-hydroxydebrisoquine) was increased significantly from 0.70 +/- 0.05 to 1.95 +/- 0.20 (P less than 0.05), while that of trimethadione (serum concentration of dimethadione/trimethadione) was not changed significantly (0.48 +/- 0.08 vs 0.41 +/- 0.06) after diltiazem treatment. Diltiazem selectively inhibits cytochrome P-450 isoenzymes.     

The pharmacokinetics of mefloquine in man: lack of effect of mefloquine on antipyrine metabolism.

A method is described for the determination of the new antimalarial agent, mefloquine, in plasma and urine. After oral administration of 750 mg mefloquine to six volunteers, absorption, was apparently slow, with plasma mefloquine concentrations at 24 h (559 +/- 181 ng ml-1; mean +/- s.d.) higher than at 6 h (459 +/- 166 ng ml-1). The elimination half-life was 373 +/- 249 h, oral clearance was 5.09 +/- 2.7 1 h-1, and apparent volume of distribution was 35.7 +/- 30.7 l kg-1 (assuming 100% bioavailability). Mefloquine (750 mg) had no significant effect on salivary kinetics of antipyrine or on the metabolic clearance of antipyrine to its three main metabolites, 3-hydroxymethylantipyrine, 4-hydroxyantipyrine and norantipyrine, when antipyrine was administered either 2 h or 2 weeks after dosing with mefloquine.     

Pharmacokinetics of molsidomine and its active metabolite, linsidomine, in patients with liver cirrhosis.

The pharmacokinetics of molsidomine were investigated in six healthy volunteers and in seven patients with alcoholic cirrhosis. After a 2 mg oral dose, molsidomine elimination half-life was prolonged in cirrhotic patients (13.1 +/- 10.0 h vs 1.2 +/- 0.2 h, P less than 0.01) because of a decrease in its apparent plasma clearance (CL/F) (39.8 +/- 31.9 ml h-1 kg-1 in patients with cirrhosis vs 590 +/- 73 ml h-1 kg-1 in volunteers). The elimination half-life of the active metabolite, linsidomine (SIN-1) was also prolonged in cirrhotic patients (7.5 +/- 5.4 h vs 1.0 +/- 0.19 h, P less than 0.05). The AUC values of both molsidomine and linsidomine were increased in the cirrhotic group, but the increase in the former was considerably greater than in the latter as shown by the significant decrease of the ratio AUClinsidomine/AUCmolsidomine x 100 (4.5 +/- 6.1 in cirrhotic patients vs 23.5 +/- 3.4 in healthy volunteers, P less than 0.001). These results suggest that liver cirrhosis profoundly alters the pharmacokinetics and metabolism of molsidomine.     

The pharmacokinetics of antipyrine in patients with graded severity of schistosomiasis.

The pharmacokinetics of antipyrine have been studied in patients with schistosomiasis. In comparison to a control group of subjects (n = 6), patients with early (active) schistosomiasis (passing live ova in urine or stools without clinical and laboratory evidence of liver involvement; n = 6) exhibited similar pharmacokinetic parameters. Of seven patients with hepatosplenic schistosomiasis (exhibiting hepatic fibrosis, splenomegaly, at least one episode of haematemesis, ascites), five showed markedly enhanced antipyrine half-life and reduced clearance. Compared to controls, the mean half-life of this group was increased from 10.9 +/- 2.4 to 19.9 +/- 9.5 h (mean +/- s.d.; P less than or equal to 0.05) and clearance reduced from 3.81 +/- 0.74 to 2.18 +/- 0.80 l h-1 (P less than or equal to 0.01). There was no change in the apparent volume of distribution. Liver biopsy was performed on all patients diagnosed as having hepatosplenic schistosomiasis in the 2 weeks prior to the antipyrine study. The results of this study indicate that hepatic microsomal metabolism is impaired in patients with advanced hepatosplenic schistosomiasis.     

Lack of relationship between debrisoquine oxidation phenotype and the pharmacokinetics of quinine.

The relationship between debrisoquine oxidation phenotype and the pharmacokinetics of quinine after a single dose (600 mg) of quinine sulphate was studied in eight extensive metabolizers (EM) and five poor metabolizers (PM). The mean elimination half-life of quinine in the PMs (10.2 +/- 1.6 (s.d.)h) was similar to that in the EMs (10.9 +/- 1.7 h). The oral clearance of quinine in the PM subjects was 0.092 +/- 0.021 l h-1 kg-1 and was not significantly different (P greater than 0.05) from that observed in the EM subjects (0.073 +/- 0.019 l h-1 kg-1). This suggests that even though quinine is extensively metabolized by oxidative biotransformation, this is carried out largely by P450 isoenzymes different from P450IID6 which oxidizes debrisoquine.     

Genetically determined oxidation capacity and the disposition of debrisoquine.

1 The disposition in urine of debrisoquine and its hydroxylated metabolites has been studied in subjects of the 'extensive metabolizer' (EM; n = 5) and 'poor metabolizer' (PM; n = 5) phenotypes. The 4-hydroxylation of debrisoquine by PM subjects following a 10 mg oral dose was capacity-limited and displayed significant dose-dependency over a range of 1-20 mg. In contrast, the EM subjects' ability to perform this metabolic oxidation did not deviate from first-order kinetics over a dose range of 10-40 mg. 2 The disposition of debrisoquine in plasma following a 10 mg oral dose has been studied in EM (n = 4) and PM (n = 3) subjects. Whilst PM subjects displayed significantly higher plasma levels of debrisoquine at all time points following 1 h post-dosing, and higher values for areas under the plasma concentration-time curve (EM: 105.6 +/- 7.0 ng ml-1 h; PM: 371.4 +/- 22.4 ng ml-1 h, 2P less than 0.0001), neither debrisoquine plasma half-life (EM: 3.0 +/- 0.5 h; PM: 3.3 +/- 0.4 h) nor renal clearance of the drug (EM: 152.8 +/- 30.3 ml min-1; PM: 137 +/- 4.5 ml min-1) displayed significant inter-phenotype differences. 3 The results of these investigations show that the phenotyping of individuals for debrisoquine oxidation status by means of a 'metabolic ratio' derived from a single 0-8 h urine sample has a sound kinetic basis. The kinetic differences between the two phenotypes would strongly suggest that the metabolic defect manifested in PM subjects is one of pre-systemic elimination capacity.     

The effect of fever on antipyrine metabolism in children.

1 The elimination of antipyrine from saliva was measured in six children aged 5 months to 5 years during fever and during a control period 2-4 weeks after the cessation of fever. 2 The mean (+/- s.d.) saliva antipyrine clearance during fever, 32 +/- 13 ml kg-1 h-1, was nearly 50% less than that when the children were afebrile, 50 +/- 22 ml kg-1 h-1 (P less than 0.02). The mean saliva antipyrine half-life during fever, 15.20 +/- 5.40 h, was almost twice as long as that found when body temperature was normal, 9.18 +/- 2.49 h (P less than 0.01). The apparent volume of distribution of antipyrine was not significantly affected by fever. 3 These findings indicate that drug metabolising ability in children is impaired during fever.     

Liver blood flow, antipyrine clearance, and antipyrine metabolite formation clearance in patients with chronic active hepatitis and alcoholic cirrhosis.

Duplex scanning was used to measure liver blood flow (hepatic artery and main branches of the portal and hepatic veins) in six healthy subjects, five cirrhotic patients, and six hepatitis patients. Antipyrine clearance and formation clearances to its metabolites were also measured. Compared with healthy control subjects, cirrhotic patients had a lower hepatic vein blood flow (-76%, P < 0.05). This was due primarily to a lower portal vein blood flow (-36%, NS). A statistically significant difference in liver blood flow between patients with hepatitis and normal subjects was not detected. Antipyrine half-life, clearance, and the area under the serum drug concentration vs time curve were significantly different in cirrhotic patients compared with the healthy subjects (mean +/- s.d.-healthy controls: t1/2 = 13.7 +/- 3.0 h, CL = 30.0 +/- 8.6 ml h-1 kg-1, AUC = 549 +/- 139 mg l-1 h; cirrhotic patients: t1/2 = 32.4 +/- 1.7 h, CL = 12.3 +/- 2.1 ml h-1 kg-1, AUC = 1061 +/- 218 mg l-1 h; P < 0.008). Antipyrine half-life, clearance, and the area under the serum drug concentration vs time curve were not significantly different in hepatitis patients compared with the healthy subjects (hepatitis patients: t1/2 = 14.3 +/- 3.7 h, CL = 29.3 +/- 8.5 ml h-1 kg-1, AUC = 498 +/- 142 mg l-1 h). The volume of distribution of antipyrine was similar in all three groups of subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of chloroquine and primaquine on antipyrine metabolism

The effects of two antimalarial drugs, chloroquine and primaquine on antipyrine kinetics and metabolism have been studied in volunteers. Chloroquine (250 mg) given 2 h before antipyrine (600 mg orally) had no effect on salivary kinetics of antipyrine or on the urinary recovery of metabolites. Primaquine (45 mg) given 2 h before antipyrine (300 mg orally), increased antipyrine half-life (calculated from 0-24 h) from 12.7 +/- 3.2 (mean +/- s.d.) to 25.3 +/- 3.9 h and decreased clearance from 3.01 +/- 0.67 to 1.32 +/- 0.32 1 h-1. There was no change in the apparent volume of distribution. Antipyrine half life changed with time in the presence of primaquine and when calculated between 24 and 48 h had returned to control. After primaquine, the metabolic clearance (calculated from 0-24 h) of antipyrine to its three main metabolites, 3-hydroxymethylantipyrine, 4-hydroxyantipyrine and norantipyrine was significantly reduced. There was no selective effect on a particular metabolic pathway. There was no change in 6 beta-hydroxycortisol excretion (expressed as a ratio of total 17-hydroxy-corticosteroids) in the period 0-48 h following primaquine administration. The inhibition of hepatic metabolism by primaquine but not the structurally related chloroquine may be an example of a structure activity phenomenon and could be of clinical significance.     

Disposition of antipyrine in African patients with Hodgkin's lymphoma.

The pharmacokinetics of antipyrine were studied in 12 healthy volunteers and 10 patients of Kenya African origin with Hodgkin's lymphoma. The half-life of antipyrine was 12.2 +/- 1.3 h (mean + s.d.), while the apparent volume of distribution (V) was 0.67 +/- 0.11 l kg-1 (mean +/- s.d.) and the total body clearance was 40.7 +/- 3.2 ml kg-1 h-1 (mean +/- s.d.) in the healthy volunteers. The antipyrine half-life in the patients with advanced Hodgkin's lymphoma was 17.1 +/- 2.7 h (mean +/- s.d.). The apparent volume of distribution was 0.72 +/- 0.14 l kg-1 (mean +/- s.d.) which was larger than in healthy volunteers (P less than 0.05). The total body clearance was 30.3 +/- 9.4 ml kg-1 h-1 (mean + s.d.) and this was reduced compared with that in healthy volunteers (P less than 0.02). After cytotoxic therapy the half-life in the patients with advanced Hodgkin's lymphoma was significantly decreased to 8.3 +/- 1.3 h (mean +/- s.d.) (P less than 0.07), and the apparent volume of distribution was reduced to 0.65 +/- 0.07 l kg-1 (mean +/- s.d.) (P less than 0.05) while the total body clearance increased to 52.8 +/- 5.5 ml kg-1 h-1 (mean +/- s.d.) (P less than 0.01).     

The effect of fever on quinine and quinidine disposition in the rat.

The pharmacokinetics of quinine and its diastereoisomer quinidine has been investigated in normal and febrile rats. Endotoxin-induced fever in rats resulted in an increased quinine clearance (CL) (4.49 +/- 1.45 vs 1.38 +/- 0.65 L h-1 kg-1, P less than 0.001) and volume of distribution (Vd) (42.6 +/- 8.8 vs 28.9 +/- 10.3 L kg-1, P less than 0.05) with a concomitant shortening of the elimination half-life (t1/2) (7.1 +/- 2.5 vs 15.9 +/- 5.9 h, P less than 0.01). With quinidine, however, fever resulted in an increased CL (3.95 +/- 1.05 vs 1.89 +/- 0.60 L h-1 kg-1, P less than 0.002) with no change in Vd and a significant decrease in t1/2 (5.1 +/- 0.7 vs 10.1 +/- 2.8 h, P less than 0.001). In both studies there was no significant difference in hepatic microsomal protein or cytochrome P450 content. Neither drug accumulated in the liver but low concentrations of quinidine were present in the heart 24 h after administration. In-vitro studies suggest that temperature does not alter the binding of either drug. These data suggest that fever enhances the clearance of quinine and quinidine. These findings may offer some additional explanation of the lack of serious quinine and quinidine toxicity during the treatment of malaria infection, even after large dosages of the drug administered during the initial period of treatment when fever is most intense.     

Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine

AIMS: In vitro studies suggest that the oxidation of quinidine to 3-hydroxyquinidine is a specific marker reaction for CYP3A4 activity. To assess the possible use of this reaction as an in vivo marker of CYP3A4 activity, we studied the involvement of cytochromes CYP2C9, CYP2E1 and CYP3A4 in the in vivo oxidative metabolism of quinidine. METHODS: An open study of 30 healthy young male volunteers was performed. The pharmacokinetics of a 200 mg single oral dose of quinidine was studied before and during daily administration of 100 mg diclofenac, a CYP2C9 substrate (n=6); 200 mg disulfiram, an inhibitor of CYP2E1 (n=6); 100 mg itraconazole, an inhibitor of CYP3A4 (n=6); 250 ml single strength grapefruit juice twice daily, an inhibitor of CYP3A4 (n=6); 250 mg of erythromycin 4 times daily, an inhibitor of CYP3A4 (n=6). Probes of other enzyme activities, caffeine (CYP1A2), sparteine (CYP2D6), mephenytoin (CYP2C19), tolbutamide (CYP2C9) and cortisol (CYP3A4) were also studied. RESULTS: Concomitant administration of diclofenac reduced the partial clearance of quinidine by N-oxidation by 27%, while no effect was found for other pharmacokinetic parameters of quinidine. Concomitant administration of disulfiram did not alter any of the pharmacokinetic parameters of quinidine. Concomitant administration of itraconazole reduced quinidine total clearance, partial clearance by 3-hydroxylation and partial clearance by N-oxidation by 61, 84 and 73%, respectively. The renal clearance was reduced by 60% and the elimination half-life increased by 35%. Concomitant administration of grapefruit juice reduced the total clearance of quinidine and its partial clearance by 3-hydroxylation and N-oxidation by 15, 19 and 27%, respectively. The elimination half-life of quinidine was increased by 19%. The caffeine metabolic index was reduced by 25%. Concomitant administration of erythromycin reduced the total clearance of quinidine and its partial clearance by 3-hydroxylation and N-oxidation by 34, 50 and 33%, respectively. Cmax was increased by 39%. CONCLUSIONS: The results confirm an important role for CYP3A4 in the oxidation of quinidine in vivo, and this applies particularly to the formation of 3-hydroxyquinidine. While a minor contribution of CYP2C9 to the N-oxidation of quinidine is possible, a major involvement of the CYP2C9 or CYP2E1 enzymes in the oxidation of quinidine in vivo is unlikely.     

The influence of alpha 1-acid glycoprotein on quinine and quinidine disposition in the rat isolated perfused liver preparation.

We have studied the effect of 0.5 and 2.0 g L-1 of alpha 1-acid glycoprotein (AAG) on the disposition of quinine and quinidine in the rat isolated perfused liver preparation. The higher concentration of AAG (2.0 g L-1) resulted in a significant decrease in clearance [quinine study (control: 9.6 +/- 2.9 vs test: 3.1 +/- 1.2 mL min-1); quinidine study (control: 9.8 +/- 2.4 vs test: 3.5 +/- 1.1 mL min-1]) and volume of distribution [quinine study (control: 1198 +/- 416 vs test: 466 +/- 95 mL); quinidine study (control: 1352 +/- 459 vs test: 317 +/- 24 mL]) but not the elimination half-life compared with control. At the lower concentration (0.5 g L-1) of AAG there was no significant difference in clearance, volume of distribution and elimination half-life for either drug compared with control. By increasing the concentration of AAG from 0.5 to 2.0 g L-1 both the hepatic extraction ratio and the fraction of drug unbound when compared with controls significantly decreased by about 66 and 60% for quinine, and by 65 and 58% for its diastereoisomer quinidine, respectively. The consequence of these changes is a substantial increase in the total quinine (or quinidine) concentrations without any change in the free quinine (or quinidine) concentrations. However, at 0.5 g L-1 AAG compared with control, no significant difference was observed in fraction of drug unbound, extraction ratio, total drug concentration or free drug concentration for either drug. In summary, changing concentrations of AAG, an important binding protein for quinine and quinidine, can affect the hepatic disposition of both drugs.     

The pharmacokinetics and pharmacodynamics of quinidine and 3-hydroxyquinidine.

1. The pharmacokinetics and pharmacodynamics of quinidine and 3-hydroxyquinidine based upon measurements of total and unbound serum concentrations were determined after a single dose (400 mg) and at steady state (200 mg every 6 h). 2. The oral clearance (7.6 +/- 1.9 vs 4.8 +/- 2.0 ml min-1 kg-1; P less than 0.05) and renal clearance (1.2 +/- 0.3 vs 0.63 +/- 0.25 ml min-1 kg-1; P less than 0.005) or quinidine were lower during steady state than after the single dose. 3. The area under the serum concentration vs time curve (AUC) of 3-hydroxyquinidine was greater at steady state than after the single dose (2.0 +/- 0.7 vs 3.0 +/- 0.6 mg l-1 h; P less than 0.05) and its renal clearance was less (3.0 +/- 1.1 vs 1.54 +/- 0.38 ml min-1 kg-1; P less than 0.05). 4. The slope of the relationship between quinidine concentration and change in QTc interval was greater at steady state (40.1 +/- 21.7 vs 72.2 +/- 41.7 ms/(mg l-1); P less than 0.05).     

Pharmacokinetics and metabolism of quinidine in extensive and poor metabolisers of sparteine

Summary The pharmacokinetics and metabolism of quinidine were investigated in extensive and poor metabolisers of sparteine. No differences in plasma clearance, terminal half life, volume of distribution or cumulative urinary excretion of quinidine, 3-hydroxyquinidine and quinidine-N-oxide were observed between phenotypes. Thus, it is unlikely that quinidine metabolism is controlled by the sparteine/debrisoquine gene locus.     

Antipyrine clearance and metabolite formation in patients with alcoholic cirrhosis.

The effect of liver cirrhosis on plasma clearance and metabolite profile of i.v. administered antipyrine was studied in 23 patients with alcoholic liver cirrhosis (age 37-70 years) and 17 healthy subjects (age 28-55 years). Liver volume was also measured and was found to be larger in patients than in controls, mean values being 1.86 and 1.36 l respectively. The elimination half-life of antipyrine in patients with alcoholic liver cirrhosis was significantly longer than in the healthy subjects (P less than 0.001). Mean values were 39.9 and 10.1 h respectively. Alcoholic liver cirrhosis had no effect on the apparent volume of distribution of antipyrine, but antipyrine plasma clearance was substantially reduced in the patients. Mean clearance values (ranges) were 13.5 (9.3-22.8) ml/min in the patients and 49.3 (31.1-103) ml/min in healthy subjects. Normalization of antipyrine plasma clearance for liver volume resulted in an only slightly increased distinction between patients and healthy subjects, mean values (ranges) being 7.8 (3.3-13.0) ml min(-1) 1(-1) and 36.1 (21.9-35.9) ml min(-1) 1(-1) respectively. The cumulative renal excretion of 4-hydroxyantipyrine (OHA) and norantipyrine (NORA) was significantly lower in patients with alcoholic liver cirrhosis than in healthy subjects, as was the total recovery of antipyrine and major metabolites from urine. Mean values were 15.0, 8.4 and 41.2% of dose in the patients respectively and 24.3, 25.8 and 68.9% of dose in the control subjects. Excreted amounts of total and unconjugated 3-hydroxymethylantipyrine (HMA) and of unchanged antipyrine were the same in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of effect of oral contraceptive use on the pharmacokinetics of quinine.

The pharmacokinetics of quinine after a single 600 mg oral dose of quinine sulphate were studied in seven female subjects who used oral contraceptives and in seven age-matched female controls who did not. There were no significant differences (P greater than 0.05) in the maximum plasma concentration (Cmax) and the time of peak concentration (tmax) between the subjects who used oral contraceptives (Cmax = 5.3 +/- 1.0 (s.d.) mg l-1; tmax = 1.4 +/- 0.7 h) and the control subjects (Cmax = 5.6 +/- 0.9 mg l-1; tmax = 2.1 +/- 0.9 h). The mean elimination half-life of quinine in the oral contraceptives user group (12.5 +/- 1.9 h) was similar (P greater than 0.05) to that in the control group (11.8 +/- 2.7 h). The oral clearance of quinine in the oral contraceptive user group was 0.133 +/- 0.055 l h-1 kg-1 (range 0.073-0.233) and was not significantly different (P greater than 0.05) from that observed in the control group (0.125 +/- 0.025 l h-1 kg-1, range 0.075-0.148).     

The contribution of genetically determined oxidation status to inter-individual variation in phenacetin disposition

The oxidative O-de-ethylation and aromatic 2-hydroxylation of phenacetin have been investigated in panels of extensive (EM, n = 13) and poor (PM, n = 10) metabolizers of debrisoquine. The EM group excreted in the urine significantly more paracetamol (EM: 40.8 +/- 14.9% dose/0-8 h; PM: 29.2 +/- 8.7% dose/0-8 h, 2P less than 0.05) and significantly less 2-hydroxylated metabolites (EM: 4.7 +/- 2.3% dose/0-8 h; PM: 9.7 +/- 3.5% dose/0-8 h, 2P less than 0.005) than the PM group. Apparent first-order rate constants, calculated from pooled phenotype data, for overall elimination of phenacetin (k) and formation of paracetamol (kml) were higher in the EM group (EM: k = 0.191 +/- 0.151 h-1; kml = 0.091 +/- 0.025 h-1; PM: k = 0.098 +/- 0.035 h-1, 2P less than 0.05, kml = 0.052 +/- 0.019 h-1, 2P less than 0.05) than the PM group. The apparent first-order rate constant for 2-hydroxylation displayed no significant inter-phenotype differences. Correlation analysis demonstrated that genetically determined oxidation status accounted for approximately 50% of the inter-individual variability in phenacetin disposition encountered in this study.     

The roles of CYP2D6 and stereoselectivity in the clinical pharmacokinetics of chlorpheniramine

AIMS: To examine the stereoselective disposition of chlorpheniramine and to evaluate the role of CYP2D6 in chlorpheniramine pharmacokinetics in humans. METHODS: Eight healthy volunteers (six extensive metabolizers with respect to CYP2D6 and two poor metabolizers) received a single 8 mg oral dose of rac-chlorpheniramine either given alone or following administration of quinidine 50 mg every 6 h for 2 days prior to the study day and every 6 h thereafter until the end of the study. Plasma concentrations of (S)-(+)- and (R)-(-)-enantiomers of chlorpheniramine were determined using liquid chromatography/mass spectrometry. RESULTS: In extensive metabolizers, mean Cmax was greater (12.55+/-1.51 ng ml-1vs 5.38+/-0.44 ng ml-1) and CLoral was lower (0.49+/-0.08 l h-1 kg-1vs 1.07+/-0.15 l h-1 kg-1) for (S)-(+)- than for (R)-(-)-chlorpheniramine (P<0.005). For (S)-(+)-chlorpheniramine, administration of quinidine, an inhibitor of CYP2D6, resulted in an increase in Cmax to 13.94+/-1.51 (P<0.01), a reduction in CLoral to 0.22+/-0.03 l h-1 kg-1 (P<0.01), and a prolongation of elimination half-life from 18.0+/-2.0 h to 29.3+/-2.0 h (P<0.001). Administration of quinidine decreased CLoral for (R)-(-)-chlorpheniramine to 0.60+/-0.10 l h-1 kg-1 (P<0.005). In CYP2D6 poor metabolizers, systemic exposure was greater after chlorpheniramine alone than in extensive metabolizers, and administration of quinidine resulted in a slight increase in CLoral. CONCLUSIONS: Stereoselective elimination of chlorpheniramine occurs in humans, with the most pharmacologically active (S)-(+)-enantiomer cleared more slowly than the (R)-(-)-enantiomer. CYP2D6 plays a role in the metabolism of chlorpheniramine in humans.     

Microsomal enzyme induction in children: the influence of carbamazepine treatment on antipyrine kinetics, 6 beta-hydroxycortisol excretion and plasma gamma-glutamyltranspeptidase activity.

1 The influence of carbamazepine (CBZ) therapy on saliva antipyrine kinetics, urinary 6 beta-hydroxycortisol excretion and plasma gamma-glutamyltranspeptidase activity was determined in nine children aged 6-14 years. 2 During 5 weeks of CBZ therapy the mean (+/- s.d.) antipyrine clearance increased from 65 +/- 12 ml kg-1 h-1 to 143 +/- 34 ml kg-1 h-1 (P less than 0.001) and the mean half-life declined from 6.24 +/- 1.23 h to 2.78 +/- 0.59 h (P less than 0.001). The apparent volume of distribution of antipyrine did not change during CBZ treatment. 3 Urinary 6 beta-hydroxycortisol excretion increased markedly during the study period from 5.10 +/- 1.77 micrograms day-1 kg-1 to 17.85 +/- 6.75 micrograms day-1 kg-1 (P less than 0.01). 4 Plasma gamma-glutamyltranspeptidase activity increased in eight out of nine children during CBZ therapy but the change was not statistically significant. 5 CBZ appears to have a marked enzyme inducing effect in young epileptics as indicated by antipyrine kinetics and 6 beta-hydroxycortisol excretion.