Y. W. Francis Lam

Principles of drug administration in renal insufficiency.

SummaryNormal renal function is important for the excretion and metabolism of many drugs. Renal diseases which affect glomerular blood flow and filtration, tubular secretion, reabsorption and renal parenchymal mass alter drug clearances and lead to the need for alterations in dosage regimens to optimise therapeutic outcome and minimise the risk of toxicity. Renal disease is increasing and the cost of care has risen progressively over the past decade. Part of these costs is related to inappropriate drug therapy and excessive drug use.Although there are a variety of methods for evaluating the various aspects of renal function, the most practical and commonly used clinical measure of renal function is estimated creatinine clearance (CLcr) as a marker for glomerular filtration. This is useful since alterations in drug clearance are proportional to alterations in CLCR, and this relationship is used as the basis for changing doses and dosage intervals for drugs which are largely renally excreted.Two populations, neonates and the elderly, are at risk of inappropriate drug dosage due to physiological changes in renal function. Estimated CLCR may not be the best method of evaluating renal function in these patients, and dosage regimens should be carefully considered. Renal insufficiency and concurrent drug therapy used in these populations can either increase or decrease drug absorption, depending on the particular agent.Drug distribution may be altered in renal insufficiency due to pH-dependent protein binding and reduced protein (primarily albumin) levels. Interestingly, renal disease may affect hepatic as well as renal drug metabolism; the exact mechanisms for these changes are not well understood. The most important quantitative pharmacokinetic change is excretion. Glomerular filtration and tubular process may both be affected but not to the same extent, and the type of renal disease may differentially affect filtration and excretion.Drug removal by dialysis is dependent on a number of factors, including the characteristics of a particular drug and the type of dialysis and equipment used. Therapeutic outcomes may be evaluated using end-points such as plasma concentrations, patient outcomes such as reduction in fever or negative cultures, and system-wide changes such as drug-use or laboratory-use patterns.

Antidepressant drug interactions and the cytochrome P450 system. The role of cytochrome P450 2D6

SummaryThe selective serotonin reuptake inhibitors (SSRIs) and venlafaxine display the following rank order of in vitro potency against the cytochrome P450 (CYP) isoenzyme CYP2D6 as measured by their inhibition of sparteine and/or dextromethorphan metabolism: paroxetine > fluoxetine ≡ norfluoxetine ≥ sertraline ≥ fluvoxamine > venlafaxine. On this basis, paroxetine would appear to have the greatest and fluvoxamine and venlafaxine the least potential for drug interactions with CYP2D6-dependent drugs. In vivo, inhibitory potency is affected by the plasma concentration of the free (unbound) drug, a potentially important consideration since many CYP2D6-metabolised drugs exhibit nonlinear (saturable) kinetics, and by the presence of metabolites, which might accumulate and interact with the CYP system. Under steady-state conditions, paroxetine and fluoxetine are approximately clinically equipotent inhibitors of CYP2D6 in vivo (as determined through their effects on desipramine metabolism); sertraline, in contrast, shows lower steady-state plasma concentrations than fluoxetine and, hence, a less pronounced inhibition of CYP2D6.Of the drugs that are metabolised by CYP2D6, secondary amine tricyclic antidepressants, antipsychotics (e.g. phenothiazines and risperidone), codeine, some antiarrhythmics (e.g. flecainide) and β-blockers form the focus of clinical attention with regard to their potential interactions with the SSRIs. Coadministration of desipramine and fluoxetine (20 mg/day) at steady-state produced an ≈ 4-fold elevation in peak plasma desipramine concentrations, while the long half-life of the active metabolite norfluoxetine was responsible for a significant and long lasting (≈ 3 weeks) elevation of plasma desipramine concentrations after discontinuation of fluoxetine. Similarly, coadministration of desipramine with paroxetine produced an ≈ 3-fold increase in plasma desipramine concentrations. In contrast, coadministration of desipramine and sertraline (50 mg/day) for 4 weeks resulted in a considerably more modest (≈ 30%) elevation in plasma desipramine concentrations. Coadministration of fluoxetine (60 mg/day, as a loading dose) [equivalent to serum concentrations obtained with 20 mg/day at steady-state] with imipramine or desipramime resulted in ≈ 3- to 4-fold increases in plasma area under the curve (AUC) values for both imipramine and desipramine (illustrating a significant drug interaction potential at multiple isoenzymes). Consistent with its minimal in vitro effect on CYP2D6, fluvoxamine shows minimal in vivo pharmacokinetic interaction with desipramine, but does interact with imipramine (≈ 3- to 4-fold increase in AUC) through inhibition of CYP3A3/4, CYP1A2, and CYP2C19. Thus, the extent of the in vivo interaction between the SSRIs and tricyclic antidepressants mirrors to a large extent their in vitro inhibitory potencies against CYP2D6 and other isoenzyme systems, especially if one takes into account pharmacokinetic factors.

CYP2D6 status of extensive metabolizers after multiple-dose fluoxetine, fluvoxamine, paroxetine, or sertraline.

The aim of this study was to evaluate the CYP2D6 inhibitory effects of four selective rerotonin re-uptake inhibitors (SSRIs). Thirty-one healthy subjects were phenotyped as extensive metabolizers using the dextromethorphan/dextrorphan (DM/DX) urinary ratio as a marker for CYP2D6 activity before and after 8 days of administration of fluoxetine 60 mg (loading dose strategy), fluvoxamine 100 mg, paroxetine 20 mg, or sertraline 100 mg in a parallel-group design. Statistical analysis was performed on log-transformed DM/DX ratios because of variability within and between treatment groups. DM/DX ratios before (DM/DX(BL)) and after (DM/DX(SSRI)) were compared within and between the four SSRI groups. DM/DX(BL) ratios were not significantly different between the four SSRI treatment groups. Comparing within groups, significant differences between DM/DX(BL) and DM/DX(SSRI) were found for the fluoxetine (p < 0.001; ratio values, 0.020 vs. 0.364) and paroxetine (p = 0.0005, ratio values 0.029 vs. 1.085) but not for the fluvoxamine or sertraline groups. Comparing between groups, significant differences in DM/DX(SSRI) ratios were found for fluoxetine versus sertraline (p = 0.0019, DM/DX = 0.364 vs. 0.057), fluoxetine versus fluvoxamine (p < 0.0001, DM/DX = 0.364 vs. 0.019), paroxetine versus sertraline (p = 0.0026, DM/DX = 1.085 vs. 0.057), and paroxetine versus fluvoxamine (p < 0.0001, DM/DX = 1.085 vs. 0.019). No significant differences were noted between the two potent CYP2D6 inhibitors, fluoxetine and paroxetine, or the two weakest inhibitors, fluvoxamine and sertraline. Five subjects in the fluoxetine and four subjects in the paroxetine groups changed to poor metabolizer phenotype (DM/DX > or = 0.3) after treatment. Although CYP2D6 inhibitory effects of fluvoxamine and sertraline did not yield significant differences from baseline, some subjects exhibited DM/DX ratio increases of 150 to 200%. One paroxetine-treated subject did not exhibit any CYP2D6 inhibition. SSRI dose and plasma concentration may be correlated with the extent of CYP2D6 inhibition and should be further investigated.

CYP2D6 Inhibition by Selective Serotonin Reuptake Inhibitors: Analysis of Achievable Steady-State Plasma Concentrations and the Effect of Ultrarapid Metabolism at CYP2D6

Study Objective. To assess the correlation between plasma concentrations of four commonly administered selective serotonin reuptake inhibitors (SSRIs) and the magnitude of cytochrome P450 (CYP) 2D6 inhibition.

Disposition and covalent binding of ibuprofen and its acyl glucuronide in the elderly

Ibuprofen is an over‐the‐counter nonsteroidal anti‐inflammatory drug with a low incidence of severe adverse reactions. It is metabolized by oxidation to carboxyibuprofen and hydroxyibuprofen and by conjugation to an acyl glucuronide. In vitro studies have indicated that ibuprofen glucuronide is labile and reactive, forming covalent adducts with proteins. To verify the formation of ibuprofen‐protein adducts in vivo, the pharmacokinetics of ibuprofen glucuronide and its covalent binding to plasma proteins were studied in five elderly patients who received long‐term administration of oral doses of ibuprofen. Plasma levels of ibuprofen glucuronide were low relative to those of ibuprofen; the ratio of area under the plasma concentration versus time curve for the glucuronide relative to the parent drug was only 4%. Covalent binding of ibuprofen to plasma protein was observed in all patients, correlating well with the area under the plasma concentration versus time curve of ibuprofen glucuronide (r = 0.966). Compared with reports for other nonsteroidal anti‐inflammatory drugs that form acyl glucuronides, plasma levels of ibuprofen‐protein adduct are low during long‐term administration. The observed lower reactivity in vivo is probably attributable to the greater stability of ibuprofen glucuronide relative to other acyl glucuronides.

Correlation of cytochrome P450 (CYP) 1A2 activity using caffeine phenotyping and olanzapine disposition in healthy volunteers.

Olanzapine has previously been shown to have predominant metabolism by cytochrome (CYP) P450 1A2. Caffeine has been shown to provide an accurate phenotypic probe for measuring CYP1A2 activity. The purpose of this study is to determine if a significant correlation exists between olanzapine disposition and caffeine metabolic ratios. Subjects were phenotyped for CYP1A2 activity with caffeine probe methodology. After 200-mg caffeine administration, blood (4 h), saliva (6 and 10 h), and urine (8 h total) were collected for high-performance liquid chromatography (HPLC) analysis of caffeine and its metabolites.CYP1A2 activity was measured as plasma (PMR4 h), saliva (SMR6 h and SMR10 h), and three urinary metabolic (UMR18 h, UMR28 h, and UMR38 h) ratios. Each of the 14 healthy nonsmokers (13 male) received a single 10 mg olanzapine dose after which blood was collected for HPLC determination of olanzapine concentrations at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, and 120 h postdose. Olanzapine pharmacokinetic parameters in this study were similar to those previously published. All caffeine metabolic ratios (PMR4 h, SMR6 h, SMR10 h, UMR18 h, and UMR28 h) significantly correlated with each other (p<0.001) except for UMR38 h, which did not correlate. A significant correlation (p<0.05) was also found between olanzapine clearance and PMR4 h (r=0.701), SMR6 h (r=0.644), SMR10 h (r=0.701), UMR18 h (r=0.745), and UMR28 h (r=0.710). A negative correlation was observed between olanzapine clearance and UMR38 h (r=−0.029, p=NS). A significant correlation was found between olanzapine clearance and various caffeine metabolic ratios. Interpatient variability in CYP1A2 activity may explain the wide interpatient variability in olanzapine disposition. Compounds that modulate CYP1A2 activity may be expected to alter olanzapine pharmacokinetics accordingly.

Stereoselectivity: An issue of significant importance in clinical pharmacology

Many drugs have one or more asymmetric centers and are administered as a racemate containing an equal mixture of enantiomers with different pharmacologic properties, routes, and rates of disposition in humans. For example, S‐warfarin is more potent than R‐warfarin, and is metabolized by different pathways. The S‐enantiomer is primarily oxidized, and the R‐enantiomer is metabolized by both oxidation and reduction. Nevertheless, because of the difficulty in separating and analyzing individual enantiomers, most pharmacokinetic and pharmacodynamic studies on drugs have been performed without considering the stereochemical factors. This is unfortunate, because a nonstereoselective approach to the study of chiral drugs precludes insight into potential valuable information that may be relevant to drug development and evaluation. On the other hand, when the pharmacologic properties (including activity, disposition, and interaction with the other enantiomer) of enantiomers have been defined, manipulation of the enantiomeric ratio or use of the pure enantiomer can be pursued to optimize therapeutic efficacy.

Pharmacodynamics and pharmacokinetics of haloperidol and reduced haloperidol in schizophrenic patients

Twelve male chronic schizophrenic inpatients, neuroleptic-free for at least 4 weeks, were given an oral test dose of 10 mg haloperidol (HAL) and reduced HAL (RHAL) in a random order, with a 2-week interval. Two weeks after the last test dose, the patients were given HAL, 5 mg orally twice daily for 7 days. Blood samples were drawn at baseline and between 0.5 and 24 hr after the test doses, and during HAL treatment as well. Plasma drug concentrations and homovanillic acid (HVA) levels were measured with high-performance liquid chromatography using electrochemical detection. HAL, but not RHAL, produced increments in plasma HVA (pHVA) levels at 24 hr after a test dose. pHVA levels remained higher than baseline during HAL treatment. Detectable interconversion between HAL and RHAL was observed in eight patients. The capacity of the reductive drug-metabolizing enzyme system, however, was greater than that of the oxidative processes. The plasma RHAL:HAL ratios on days 6 and 7 were higher than and positively correlated with those at Tmax after a single dose of HAL and were negatively correlated with the HAL:RHAL ratios at Tmax after a single dose of RHAL. Thus, both reductive and oxidative drug-metabolizing systems probably contribute to individual differences in plasma RHAL:HAL ratios in HAL-treated schizophrenic patients.

Reversible metabolism of haloperidol and reduced haloperidol in Chinese schizophrenic patients

Haloperidol disposition has been associated with reversible metabolism: it is reversibly reduced to its metabolite, reduced haloperidol, which has less pharmacologic activity than the parent compound. To characterize the interconversion process, six healthy male schizophrenics were administered a single dose of 10 mg haloperidol or reduced haloperidol in a randomized crossover manner. Using a general pharmacokinetic model for the interconversion process, the clearances of haloperidol and reduced haloperidol are 1.15±0.32 l/h/kg and 0.76±54 l/h/kg, respectively. These clearances are similar to that obtained by the usual mammillary model analysis. With a single 10 mg dose administration of either drug, about 23% of the biotransformation of haloperidol involves the reduction pathway. Back conversion from the reduced metabolite to the parent drug through oxidation contributes even less to the total biotransformation of reduced haloperidol. This action of interconversion or saturation under chronic drug administration is unknown. Reversible metabolism of haloperidol could partially account for the wide therapeutic range for haloperidol as reported in the literature.

Comparison of haloperidol and reduced haloperidol plasma levels in four different ethnic populations

1. Plasma haloperidol and reduced haloperidol concentration were measured in four ethnic populations. 2. Plasma samples were obtained under steady-state conditions and obtained 10-12 hours post bedtime dose and prior to the morning dose. 3. Haloperidol and reduced haloperidol plasma levels were assayed by radioimmunoassay and liquid chromatography. 4. A wide interpatient variability between haloperidol dose and plasma concentration was observed for each ethnic group. 5. The Chinese group differed from the other ethnic populations. 6. A nonlinear relationship was observed between haloperidol and reduced haloperidol plasma levels in each ethnic group. Further, the relationship of haloperidol to reduced haloperidol plasma levels differed for each ethnic group. These results suggest that various ethnic groups could metabolize haloperidol and reduced haloperidol differently.