Gershwin T. Blyden

Trazodone kinetics: Effect of age, gender, and obesity

Single 25 mg intravenous and 50 mg oral doses of trazodone were given to 43 healthy subjects, divided into young men and women (aged 18 to 40 years) and elderly men and women (aged 60 to 76 years). Among men, trazodone volume of distribution (Varea) was increased in elderly vs. young subjects (1.15 vs. 0.89 L/kg; P < 0.05), and clearance decreased (1.65 vs. 2.31 ml/min/kg; P < 0.05), thereby increasing elimination half‐life (t½) in elderly men (8.2 vs. 4.7 hours; P < 0.001). Varea in women was also increased in the elderly (1.5 vs. 1.27 L/kg; P < 0.02), causing increased t½ (7.6 vs. 5.9 hours; P < 0.05), but clearance was unrelated to age. Absolute bioavailability of oral trazodone averaged 70% to 90% and was unrelated to age or sex. In 23 obese subjects (mean weight 112 kg) vs. 23 matched control subjects of normal weight (mean 65 kg), Varea was greatly increased (162 vs. 67 L; 1.43 vs. 1.04 L/kg; P < 0.001) and was highly correlated with body weight (r = 0.91). Clearance was unchanged between groups (146 vs. 136 ml/min), but the increased Varea caused prolonged t½ in obese subjects (13.3 vs. 5.9 hours; P < 0.001). Reduced clearance of trazodone among elderly men may indicate a need for dosage reduction during chronic therapy. In obese individuals, choice of dosage during chronic treatment should be based on ideal rather than total body weight.

Pharmacokinetics of Diphenhydramine and a Demethylated Metabolite Following Intravenous And Oral Administration

Ten healthy volunteers received a single 50‐mg dose of diphenhydramine (DP) hydrochloride intravenously and orally on two separate occasions. Kinetics of DP and a major demethylated metabolite (DMDP) were determined from multiple plasma samples drawn during a 24‐ to 48‐hour period after dosage. Modification of a gas chromatographic (GC) technique allowed simultaneous quantitation of DP and DMDP. Mean kinetic variables for DP after intravenous (IV) dosage were: volume of distribution, 4.5 L/kg; elimination half‐life, 8.4 hours; clearance, 6.2 mL/min/kg. After oral DP administration, a peak plasma level of 66 ng/mL was reached 2.3 hours after dosage. Systemic availability was 72%, nearly identical to the predicted estimate (71%) based on clearance of IV DP relative to hepatic blood flow. Appearance of the metabolite, DMDP, mirrored disappearance of DP; the area under the plasma concentration‐time curve (AUC) for DMDP was highly correlated (r = .79, P < .05) with clearance of IV DP. However, metabolite AUC was significantly higher after oral as opposed to IV DP (218 vs 145 hr‐ng/mL, P < .05). Because DP and DMDP elute nearly identically on standard GC systems, methodologic modifications are needed to resolve them. Coelution of the two compounds could bias kinetic data based on plasma concentration presumed to be specific for intact DP.

Metronidazole Impairs Clearance of Phenytoin but Not of Alprazolam or Lorazepam

Healthy volunteers received single doses of either phenytoin (300 mg IV), alprazolam (1 mg orally) or lorazepam (2 mg IV) on two occasions in random sequence. One of the two trials was a control; for the other trial, subjects ingested metronidazole, 250 mg three times daily beginning 4 days prior to and continuing for the duration of each kinetic study. Compared with control, metronidazole significantly prolonged phenytoin half‐life (23 versus 16 hours, P < .02) and reduced its clearance (.28 versus .33 mL/min/kg, P < .005), known to depend on aromatic hydroxylation. However, metronidazole did not significantly alter kinetic variables for either alprazolam (metabolized by aliphatic hydroxylation) or lorazepam (metabolized by glucuronide conjugation). Thus, metronidazole has the capacity to impair the clearance of certain oxidatively metabolized drugs, but there is no apparent way to predict which drugs will be so influenced.

Differential Effect of Cigarette Smoking on Antipyrine Oxidation versus Acetaminophen Conjugation

The effect of cigarette smoking on drug oxidation and conjugation was studied using antipyrine and acetaminophen as marker compounds. For the antipyrine study, healthy cigarette smokers (n = 30) and nonsmoking controls (n = 53) received a single 1.0-gram intravenous dose of antipyrine. For the acetaminophen study, 14 smokers and 15 nonsmokers received a 650-mg intravenous dose of acetaminophen. The clearance of antipyrine was significantly increased (0.93 vs. 0.60 ml/min/kg, p less than 0.0001) and elimination half-life was correspondingly reduced (8.9 vs. 13.0 h, p less than 0.0001) in smokers compared to nonsmoking controls. Total recovery of antipyrine and metabolites excreted in urine did not differ between groups, but there was a significantly increased fractional clearance of antipyrine via formation of 4-hydroxyantipyrine and 3-hydroxymethyl metabolites in smokers. Fractional clearance via formation of norantipyrine did not differ significantly between groups. Comparison of acetaminophen kinetics between smokers and nonsmokers indicated no significant differences in elimination half-life, clearance or volume of distribution. Thus, cigarette smoking is more likely to induce drug oxidation rather than drug conjugation. However, not all oxidative pathways are equally influenced; induction effects of smoking are highly substrate selective and pathway specific.

Lack of Effect of Influenza Vaccine on the Pharmacokinetics of Antipyrine, Alprazolam, Paracetamol (Acetaminophen) and Lorazepam

Summary31 healthy male (n = 17) and female (n = 14) volunteers, aged 20 to 45 years, were divided into 4 groups and received on 3 separate occasions either: paracetamol (acetaminophen) 650mg intravenously (n = 9); alprazolam 1mg orally (n = 7); antipyrine (Phenazone) 1g intravenously (n = 8); or lorazepam 2mg intravenously (n = 7). Doses were administered prior to influenza vaccine (0.5ml, intramuscularly) and at 7 and 21 days post-vaccination. The overall differences among the 3 trials in clearance of antipyrine were of borderline significance (p < 0.0611), with a trend towards reduced clearance in both of the post-vaccination trials. There were no overall differences observed in the elimination half-life of antipyrine, nor were there significant differences between trials in cumulative urinary excretion or fractional recovery of intact antipyrine, 4-hydroxyantipyrine, norantipyrine. or 3-hydroxymethyl antipyrine. For paracetamol and alprazolam, there were no significant differences among the 3 trials in any of the kinetic variables. The elimination half-life of lorazepam varied significantly among trials, but differences were small and not systematic. Lorazepam clearance did not vary significantly among trials. Thus, clearance of drugs which undergo hepatic conjugative reactions such as glucuronidation and sulphation are unlikely to be affected by the coadministration of influenza vaccine. Furthermore, not all drugs which are biotransformed by hepatic microsomal oxidation necessarily have impaired clearance due to coadministration of influenza vaccine.

Antipyrine and Lidocaine Are Cleared Faster in Horses than in Humans: Acetaminophen May Be Handled Similarly

The following studies were designed to evaluate plasma elimination kinetics of intravenously administered antipyrine, acetaminophen and lidocaine among 9 healthy adult horses and 9 healthy drug-free humans (3 each per drug group), in order to compare potential species differences in drug-metabolizing ability. Acetaminophen is largely biotransformed in humans by hepatic glucuronide and sulfate conjugation, whereas both antipyrine and lidocaine are oxidized by hepatic microsomal mixed-function oxidases. Thus, plasma clearances of these drugs are thought to reflect differences in hepatic oxidative and conjugative activity, and possibly hepatic blood flow in the case of lidocaine. Results showed that mean (+/- SD, n = 3) acetaminophen clearance was similar in both horses (4.84 +/- 0.637 ml/min/kg) and humans (4.68 +/- 0.691 ml/min/kg). However, antipyrine clearance was 10 times greater in horses (5.83 +/- 2.21 ml/min/kg) than in humans (0.536 +/- 0.110 ml/min/kg), which may reflect enhanced hepatic microsomal activity in horses. Although lidocaine clearance in humans was similar to estimated hepatic blood flow (20.6 +/- 5.81 ml/min/kg), clearance in horses was more than 2 times greater (52.0 +/- 11.7 ml/min/kg). The cause of the higher clearance of lidocaine in horses (like dogs) remains unexplained, and may involve significant metabolism of lidocaine at extrahepatic, extravascular sites, for intravascular degradation and renal excretion of intact lidocaine in horses was negligible. Although precise biochemical mechanisms underlying pharmacokinetic parameters for these drugs in horses were not determined, it is nonetheless concluded from antipyrine results that horses may have an enhanced ability (compared with humans) to clear drugs from the circulation that are primarily metabolized in the liver by phase I oxidative reactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Large Theophylline Requirements due to High Theophylline Clearance: Verification by the Antipyrine Test

An asthmatic patient required very high doses of theophylline (2.88 g/day by intravenous infusion) to maintain an adequate serum theophylline concentration (12 micrograms/ml). His cigarette smoking and concurrent treatment with phenytoin were suspected to have produced hepatic microsomal enzyme induction, causing unusually high theophylline clearance. The intravenous antipyrine test demonstrated an unusually short half-life (5.5 h) and high clearance (95 ml/min) of antipyrine, consistent with induced clearance of antipyrine. Formation of the 4-hydroxy metabolite of antipyrine was disproportionately induced. Thus the antipyrine test can be of clinical value for documenting hepatic microsomal enzyme induction in patients with low steady-state theophylline concentrations despite high maintenance doses.

Acetaminophen pharmacokinetics in women receiving conjugated estrogen.

Acetaminophen is biotransformed by glucuronide and sulfate conjugation and is used as an index compound to evaluate factors that may potentially influence drug conjugation capacity [1]. Conjugated estrogens are commonly used for the treatment of vasomotor symptoms associated with menopause, as replacement therapy in hypergonadism, and for estrogen-deficiency-induced osteoporosis. Because the metabolic clearance of several drugs is altered by low-dose estrogen-containing oral contraceptive preparations and conjugated estrogens, the possibility of a pharmacokinetic interaction exists between conjugated estrogens and drugs that undergo glucuronide and sulfate conjugation [2-9]. Thus, we evaluated the effect of chronic conjugated estrogen use on acetaminophen pharmacokinetics. Thirty healthy female volunteers participated after giving written informed consent. Twelve of the women had been taking a conjugated estrogen preparation for at least 3 or more months prior to the study for at least 3 or 4 weeks per month. A control group consisted of 18 women were not taking conjugated estrogens. The two groups were matched as closely as possible for age and body weight (Table 1). All subjects were healthy, active, ambulatory adults with no history of medical disease and who were taking no other medications except as described above. Acetaminophen (650 mg) was administered by constant intravenous infusion over a 5-rain period [10]. Venous blood samples were drawn from the contralateral arm into heparinized tubes at multiple time points during 24 h after drug administration. Samples were centrifuged and the plasma was separated and stored at 20 °C until the time of assay. Concentrations of acetaminophen in all samples were determined by high-presgure liquid chromatography [10]. Pharmacokinetic variables for acetaminophen were determined by iterative nonlinear least-squares regression analysis [11]. Differences in acetaminophen kinetic variables between control subjects and conjugated estrogen recipients were analyzed with an unpaired Students t-test. There were no significant differences between groups in acetaminophen volume of distribution, elimination half-life, or clearance (Table 1). When only the non-smokers in each group were analyzed, there still was no significant difference between controls and conjugated estrogen users in acetaminophen clearance. Conjugated estrogens and low-dose estrogen-containing oral contraceptive preparations have a variable effect on metabolic clearance of drugs biotransformed by oxidation and conjugative mechanisms [2-9]. Since prophylactic conjugated estrogen use may prevent osteoporosis and associated vertebral and various osteoporotic fractures, it is important to identify and quantitate any changes in drug metabolizing activity that may be associated with conjugated estrogen therapy. In this study, conjugated estrogen use did not alter acetaminophen pharmacokinetics, although low-dose estrogen-containing oral contraceptives has been reported to enhance the metabo-

Antipyrine pharmacokinetics in women receiving conjugated estrogens.

The pharmacokinetics of a single 1.0 to 1.2‐g intravenous dose of antipyrine was studied in 22 healthy female volunteers aged 28 to 70 years (mean, 45 years). Eleven subjects had been taking a conjugated estrogen preparation for at least 3 months; the other 11 subjects who were not taking conjugated estrogens and who were matched for age, weight, and smoking patterns, served as a control group. Plasma antipyrine concentrations were determined by high‐pressure liquid chromatography (HPLC) in multiple plasma samples drawn 24 to 48 hours after dosage. Mean ± SE pharmacokinetic variables in control and conjugated‐estrogen groups were volume of distribution, 0.57 ± 0.02 versus 0.56 ± 0.02 L/kg; elimination half‐life, 11.0 ± 0.82 versus 12.6 ± 0.89 hours; and clearance, 0.63 ± 0.06 versus 0.54 ± 0.03 mL/min/kg. None of the differences was significant. Although antipyrine clearance is significantly impaired by oral contraceptives, there is no evidence of altered antipyrine pharmacokinetics from treatment with conjugated estrogens.

Cyclosporine Blood Concentrations Determined by Specific Versus Nonspecific Assay Methods

Cyclosporine blood concentrations were simultaneously determined by radioimmunoassay (RIA) and high‐performance liquid chromatography (HPLC) at multiple points in time in two patients receiving cyclosporine for immunosuppression following liver transplantation. Radioimmunoassay levels always exceed those determined by HPLC; however, the divergence between the two methods increased as serum bilirubin concentration increased, with HPLC:RIA ratios generally less than 0.3 when serum bilirubin concentrations exceeded 10.0 mg/dL. These preliminary results suggest that retention of immunoactive cyclosporine metabolites due to impaired liver function may account for RIA‐determined cyclosporine concentrations that greatly exceed those measured by HPLC.