Interindividual variability of CYP2C19-catalyzed drug metabolism due to differences in gene diplotypes and cytochrome P450 oxidoreductase content.

Large interindividual variability has been observed in the metabolism of CYP2C19 substrates in vivo. The study aimed to evaluate sources of this variability in CYP2C19 activity, focusing on CYP2C19 diplotypes and the cytochrome P450 oxidoreductase (POR). CYP2C19 gene analysis was carried out on 347 human liver samples. CYP2C19 activity assayed using human liver microsomes confirmed a significant a priori predicted rank order for (S)-mephenytoin hydroxylase activity of CYP2C19*17/*17 > *1B/*17 > *1B/*1B > *2A/*17 > *1B/*2A > *2A/*2A diplotypes. In a multivariate analysis, the CYP2C19*2A allele and POR protein content were associated with CYP2C19 activity. Further analysis indicated a strong effect of the CYP2C19*2A, but not the *17, allele on both metabolic steps in the conversion of clopidogrel to its active metabolite. The present study demonstrates that interindividual variability in CYP2C19 activity is due to differences in both CYP2C19 protein content associated with gene diplotypes and the POR concentration.The Pharmacogenomics Journal advance online publication, 1 September 2015; doi:10.1038/tpj.2015.58.

Grapefruit juice, a glass full of drug interactions?

Numerous reports have documented drug interactions with grapefruit juice (GFJ) that occur via inhibition of CYP3A enzymes. As reported by Glaeser et al. in the March 2007 issue of this journal, there is increasing recognition that GFJ may also affect the activity of influx (e.g., OATPs) and efflux (e.g., P-glycoprotein) transporters. This commentary focuses on these interactions between GFJ and drug transporters.

Transport vs. Metabolism: What Determines the Pharmacokinetics and Pharmacodynamics of Drugs? Insights From the Extended Clearance Model.

The well-stirred hepatic clearance model (WSHM) has been expanded to include drug transporters (i.e., extended clearance model [ECM]). However, the consequences of this expansion in understanding when transporters vs. metabolic enzymes will affect the pharmacokinetic (PK) and pharmacodynamic (PD) of drugs remains opaque. Identifying the rate-determining step(s) in systemic or tissue drug PK/PD will allow accurate predictions of drug PK/PD and drug-drug interactions (DDIs). Here, we clarify the implications of the ECM on PK/PD of drugs.

Ontogeny of Hepatic Drug Transporters as Quantified by LC-MS/MS Proteomics.

Protein expression of major hepatic uptake and efflux drug transporters in human pediatric (n = 69) and adult (n = 41) livers was quantified by liquid chromatography / tandem mass spectroscopy (LC-MS/MS). Transporter protein expression of OCT1, OATP1B3, P-gp, and MRP3 was age-dependent. Particularly, significant differences were observed in transporter expression (P < 0.05) between the following age groups: neonates vs. adults (OCT1, OATP1B3, P-gp), neonates or infants vs. adolescents and/or adults (OCT1, OATP1B3, and P-gp), infants vs. children (OATP1B3 and P-gp), and adolescents vs. adults (MRP3). OCT1 showed the largest increase, of almost 5-fold, in protein expression with age. Ontogenic expression of OATP1B1 was confounded by genotype and was revealed only in livers harboring SLCO1B1*1A/*1A. In livers >1 year, tissues harboring SLCO1B1*14/*1A showed 2.5-fold higher (P < 0.05) protein expression than SLCO1B1*15/*1A. Integration of these ontogeny data in physiologically based pharmacokinetic (PBPK) models will be a crucial step in predicting hepatic drug disposition in children.

The concept of fraction of drug transported (ft ) with special emphasis on BBB efflux of CNS and antiretroviral drugs.

The fraction of drug transported (ft) into or out of a tissue is a concept useful to understand the impact of transporters on absorption, distribution, metabolism, and excretion (ADME) and tissue distribution of a drug. Here, ft is utilized to explain the impact of transporters on central nervous system (CNS) distribution of drugs, drug interactions (DDI), and to predict the unbound brain concentration (Cu,b) of the drug. The latter is important to ascertain if Cu,b is sufficient for efficacy.

Pharmacokinetics of oral zidovudine (azidothymidine) in patients with AIDS when administered with and without a high-fat meal.

Zidovudine is the only drug currently approved for the treatment of HIV infection. The present recommended doses found to be efficacious in patients with AIDS (200 mg every 4 h) achieve serum zidovudine concentrations greater than 0.267 micrograms/ml (1 mumol/l). Since patients often take zidovudine with food, we have investigated the effect of a liquid high-fat meal on the rate of absorption of zidovudine and on the peak serum concentration achieved. Eight patients received their usual dose of zidovudine (100 mg or 250 mg), with and without a liquid high-fat meal, on two separate study days, in a randomized crossover fashion. Blood and urine samples were collected over a 4-h period. In the absence of food, zidovudine is rapidly absorbed; the time to reach maximal serum concentration (Tmax) was 0.68 (+/- 0.25) h and the mean peak serum concentration (Cmax) achieved was 0.49 (+/- 0.3) micrograms/ml (dose normalized to 100 mg dose). In the presence of a high-fat meal, Tmax was significantly prolonged [1.95 (+/- 0.69) h; P less than 0.05] and the Cmax reduced [0.245 (+/- 0.12) micrograms/ml; P less than 0.05]. This demonstrates that to achieve maximal zidovudine serum concentrations, patients should take this medication on an empty stomach.

Simultaneous modeling of pharmacokinetics and pharmacodynamics with nonparametric kinetic and dynamic models.

Three models, linked in series, can be used to analyze combined pharmacokinetic (PK) and pharmacodynamic (PD) data arising from non--steady-state experiments. A PK model relates dose to plasma drug concentration (Cp); a link model relates Cp to drug concentration at the effect site (Ce); and a PD model relates Ce to drug effect (E). All three submodels can be stated parametrically. Recently the use of a nonparametric PD submodel has been proposed (CLIN PHARMACOL THER 1984;35:733-41). In this article we use an extended nonparametric approach that represents both the PK and PD models nonparametrically, but retains a parametric link model. Cp data from several PK models and E data from several PD models were simulated. After the addition of noise to both the Cp and E data, they were analyzed by both the parametric and extended nonparametric methods. The methods were compared by how well they estimated the PD model. To assess robustness, the effect of misspecification of the PK submodel on the goodness of estimation of both methods was also compared. In the absence of model misspecification, the parametric method usually estimates the PD model better than the nonparametric method. However, this difference in the performances diminishes and even reverses when the PK model is misspecified. Because one can rarely be certain that model misspecification is absent, the nonparametric approach may offer a distinct advantage for routine analysis of PK/PD data.

Disposition of drugs in cystic fibrosis. VII. Acetylation of sulfamethoxazole in blood cells: in vitro-in vivo correlation and characterization of its kinetics of acetylation in lymphocytes.

OBJECTIVE: To determine if acetylation of sulfamethoxazole in blood cells is a surrogate measure of its acetylation in vivo. If it is, to use these cells to determine the mechanism(s) by which acetylation of sulfamethoxazole is enhanced in cystic fibrosis. METHODS: Single-point sulfamethoxazole acetylation activity in blood cells obtained from patients with cystic fibrosis (n = 6) and control subjects (n = 7) who had previously participated in our in vivo study was determined. The parameters, Vmax and Km, for acetylation of sulfamethoxazole in lysed lymphocytes obtained from patients with cystic fibrosis (n = 6) and control subjects (n = 5) were also determined. RESULTS: The acetylation activity in cystic fibrosis whole blood, lysed erythrocytes, and lysed peripheral blood mononuclear cells was significantly (p < 0.05) greater than that in cells obtained from control subjects and was highly correlated with acetylation of sulfamethoxazole in vivo (r > 0.80). The apparent Vmax for cystic fibrosis lymphocyte lysate was significantly (p < 0.05) greater than that obtained for control lymphocyte lysate (72.99 +/- 9.07 versus 60.97 +/- 2.26 pmol/mg protein/min), and the apparent Km was significantly (p < 0.05) lower (0.51 +/- 0.07 versus 0.73 +/- 0.06 mmol/L). CONCLUSION: Blood cells may be used as surrogate markers to elucidate the mechanism(s) by which acetylation of sulfamethoxazole (catalyzed by the monomorphic N-acetyltransferase) is enhanced in subjects with cystic fibrosis. Both activation or activation and induction of the monomorphic N-acetyltransferase should be considered as possible mechanism(s) to explain this phenomenon.

Disposition of drugs in cystic fibrosis. I. Sulfamethoxazole and trimethoprim.

The disposition of sulfamethoxazole and trimethoprim, after constant rate intravenous administration (10 mg/kg/hr sulfamethoxazole and 2 mg/kg/hr trimethoprim for 1 hour), was investigated in adult patients with cystic fibrosis (n = 7) and in age-matched healthy subjects (control subjects, n = 8). The total plasma clearance of sulfamethoxazole was found to be increased in cystic fibrosis (0.0262 +/- 0.0064 L/hr/kg) when compared with that found in control subjects (0.0188 +/- 0.0043 L/hr/kg). This increase in clearance was found to be primarily attributable to an increase in the metabolic clearance of sulfamethoxazole to N4-acetylsulfamethoxazole (0.00903 +/- 0.00247 versus 0.00355 +/- 0.00049 L/hr/kg) with the renal clearance of sulfamethoxazole remaining unchanged. These conclusions were not altered when the pharmacokinetic parameters were computed for the unbound drug or when they were normalized with respect to body surface area. These data indicate that, in cystic fibrosis, the enzymes mediating the metabolism of sulfamethoxazole to N4-acetylsulfamethoxazole, N-acetyltransferase(s), may be induced, activated, or both, or that the uptake of sulfamethoxazole by cells that metabolize sulfamethoxazole to N4-acetylsulfamethoxazole is enhanced. The total plasma clearance of trimethoprim was also found to be increased in cystic fibrosis (0.1808 +/- 0.0440 L/hr/kg) when compared with that found in control subjects (0.1139 +/- 0.0193 L/hr/kg). In contrast to sulfamethoxazole, this increase in clearance was found to be primarily attributable to an increase in the renal clearance of trimethoprim (0.1240 +/- 0.0299 versus 0.0720 +/- 0.0166 L/hr/kg). These data indicate that the tubular secretion of trimethoprim may be enhanced in cystic fibrosis.

Disposition of drugs in cystic fibrosis. IV. Mechanisms for enhanced renal clearance of ticarcillin.

To investigate the hypothesis that renal secretion of penicillins is enhanced in cystic fibrosis the maximal tubular secretion rate (Tmax) of ticarcillin and the serum concentration of ticarcillin at half-maximal secretion rate (TC50) were determined in patients with cystic fibrosis (n = 6) and control subjects (n = 6). Each subject received three consecutive constant-rate intravenous infusions of ticarcillin (4, 13, and 70 mg/kg/hr; 2 1/2 hours each) simultaneously with a constant-rate (30 mg/kg/hr) infusion of insulin. Urine samples were collected at 1/2-hour intervals and serum samples at the midpoint of the urine collections. Ticarcillin and inulin concentrations in serum and urine were determined by high-performance liquid chromatographic and a spectrophotometric method, respectively. Ticarcillin serum protein binding was determined by ultrafiltration. Steady-state ticarcillin serum concentrations were achieved at all three infusion rates. The TC50 was significantly lower (p < 0.05) in patients with cystic fibrosis (33.7 +/- 12.2 micrograms/ml) compared with that in control subjects (77.6 +/- 38.4 micrograms/ml). In contrast, the Tmax was similar (cystic fibrosis, 0.25 +/- 0.12 mg/min/kg; control, 0.22 +/- 0.14 mg/min/kg; p > 0.05). These data indicate that renal clearance of penicillins is enhanced in cystic fibrosis because of greater affinity of the renal secretory system for these drugs.

Disposition of drugs in cystic fibrosis. V. In vivo CYP2C9 activity as probed by (S)-warfarin is not enhanced in cystic fibrosis.

Enhanced metabolism of theophylline in subjects with cystic fibrosis suggests that the activity of certain cytochrome P450 isoforms is affected in subjects with this genetic disease. To determine whether this effect on the P450 enzymes is selective, the in vivo activity of the cytochrome P450 isoform CYP2C9 was determined in adult subjects with cystic fibrosis (n = 6) and in control subjects (n = 8). Subjects were administered (S)-warfarin as a single intravenous bolus dose (0.375 mg/kg), and urine and plasma samples were collected for 96 hours. Plasma (S)-warfarin concentrations were determined by HPLC; urinary concentrations of (S)-warfarin and its metabolites were determined by gas chromatography-mass spectrometry. The total plasma clearance of (S)-warfarin (subjects with cystic fibrosis, 3.6 +/- 0.48 ml/hr/kg; control subjects, 3.82 +/- 0.73 ml/hr/kg), elimination half-life (subjects with cystic fibrosis, 29.5 +/- 4.2 hours; control subjects, 25.9 +/- 5.4 hours); and steady-state volume of distribution (subjects with cystic fibrosis, 153 +/- 18 ml/kg; control subjects, 138 +/- 22 ml/kg) were similar in the two groups (p > 0.05). The metabolic clearance of (S)-warfarin to its major metabolites mediated by CYP2C9, 6-hydroxywarfarin and 7-hydroxywarfarin, was not significantly (p > 0.05) different between the two groups (6-hydroxywarfarin: subjects with cystic fibrosis, 0.33 +/- 0.1 ml/hr/kg; control subjects, 0.41 +/- 0.1 ml/hr/kg; 7-hydroxywarfarin: subjects with cystic fibrosis, 1.34 +/- 0.49 ml/hr/kg; control subjects, 1.8 +/- 0.45 ml/hr/kg). On the basis of these data, we conclude that the in vivo cytochrome P450 activity is selectively affected in persons with cystic fibrosis.

Disposition of drugs in cystic fibrosis. III. Acetaminophen.

The disposition of acetaminophen after oral administration was investigated in adults with cystic fibrosis (n = 5) and in age-matched healthy control subjects (n = 5). The total plasma clearance of acetaminophen was found to be greater (p less than 0.025) in subjects with cystic fibrosis (0.362 +/- 0.081 L/hr/kg) than in control subjects (0.247 +/- 0.022 L/hr/kg). This difference in clearance was found to be primarily attributable to a greater metabolic clearance of acetaminophen to acetaminophen sulfate (0.080 +/- 0.023 L/hr/kg for subjects with cystic fibrosis and 0.045 +/- 0.008 L/hr/kg for control subjects; p less than 0.05) and to a greater metabolic clearance of acetaminophen to acetaminophen glucuronide (0.189 +/- 0.051 L/hr/kg for subjects with cystic fibrosis and 0.114 +/- 0.017 L/hr/kg for control subjects; p less than 0.05) in persons with cystic fibrosis. Of the mechanisms that may be responsible for these differences, the most likely is enhanced activity (in subjects with cystic fibrosis) of the transferases that mediate the metabolism of acetaminophen to acetaminophen sulfate and acetaminophen glucuronide, respectively.

Disposition of drugs in cystic fibrosis. II. Hepatic blood flow.

To determine whether the increased clearance of high extraction-ratio drugs in cystic fibrosis is caused by an increase in hepatic blood flow, the blood flow in main branches of the hepatic vein and portal vein was measured by use of noninvasive duplex ultrasound scanning in 10 adult subjects with cystic fibrosis and in 10 healthy age-, gender-, and height-matched control subjects. No statistically significant differences between subjects with cystic fibrosis and control subjects were detected in either the hepatic vein (217 +/- 103 ml/min for subjects with cystic fibrosis versus 211 +/- 135 ml/min for control subjects) or the portal vein (205 +/- 114 ml/min for subjects with cystic fibrosis versus 190 +/- 101 ml/min for control subjects) blood flows. These data indicate that a large (greater than or equal to 100%) increase in the clearance of high extraction-ratio drugs in patients with cystic fibrosis is unlikely to be primarily caused by an increase in hepatic blood flow. It is probable that alternative mechanisms such as enhanced secretory or metabolic pathways account in large part for increases in clearance of high extraction-ratio drugs.

Disposition of drugs in cystic fibrosis. VI. In vivo activity of cytochrome P450 isoforms involved in the metabolism of (R)-warfarin (including P450 3A4) is not enhanced in cystic fibrosis.

OBJECTIVE: To determine whether the activity of cytochrome P450 isoforms involved in the metabolism of (R)-warfarin is enhanced in cystic fibrosis. DESIGN: Six adult subjects with cystic fibrosis and six healthy control subjects, matched by age and sex, were administered (R)-warfarin as a single intravenous bolus dose (0.375 mg/kg), and urine and plasma samples were collected for 192 hours. The concentration of (R)-warfarin in plasma and the concentration of (R)-warfarin and its metabolites in urine were determined by HPLC and GC/MS, respectively. Plasma protein binding of (R)-warfarin was measured by ultrafiltration. RESULTS: The unbound plasma clearance of (R)-warfarin was not significantly (p > 0.05) different between the cystic fibrosis and the control groups (cystic fibrosis, 997 +/- 483 ml/hr/kg; control, 788 +/- 219 ml/hr/kg). The unbound metabolic clearances of (R)-warfarin to its oxidative metabolites--6-hydroxywarfarin, 7-hydroxywarfarin, 8-hydroxywarfarin, and 10-hydroxywarfarin (mediated by P450 3A4)--were also similar (p > 0.05) in the two groups (6-hydroxywarfarin: cystic fibrosis: 124.2 +/- 72.8 ml/hr/kg, control: 99.4 +/- 37.3 ml/hr/kg; 7-hydroxywarfarin: cystic fibrosis: 43.8 +/- 32.2 ml/hr/kg, control: 34.5 +/- 10.6 ml/hr/kg; 8-hydroxywarfarin: cystic fibrosis: 80.4 +/- 85.4 ml/hr/kg, control: 69.5 +/- 39.5 ml/hr/kg; 10-hydroxywarfarin: cystic fibrosis: 4.38 +/- 2.72 ml/hr/kg, control: 16.28 +/- 13.71 ml/hr/kg). CONCLUSION: The in vivo activity of cytochrome P450 isoforms involved in the metabolism of (R)-warfarin, including P450 3A4, is not enhanced in cystic fibrosis.

Metabolism of dapsone to its hydroxylamine by CYP2E1 in vitro and in vivo.

Dapsone toxicity is putatively initiated by formation of a hydroxylamine metabolite by cytochromes P450. In human liver microsomes, the kinetics of P450-catalyzed N-oxidation of dapsone were biphasic, with the Michaelis-Menten constants of 0.14 +/- 0.05 and 0.004 +/- 0.003 mmol/L and the respective maximum velocities of 1.3 +/- 0.1 and 0.13 +/- 0.04 nmol/mg protein/min (mean +/- SEM). Troleandomycin (40 mumol/L) inhibited hydroxylamine formation at 100 mumol/L dapsone by 50%; diethyldithiocarbamate (150 mumol/L) and tolbutamide (400 mumol/L) inhibited at 5 mumol/L dapsone by 50% and 20%, respectively, suggesting that the low-affinity isozyme is CYP3A4 and the high-affinity isozymes are 2E1 and 2C. Disulfiram, 500 mg, 18 hours before a 100 mg oral dose of dapsone in healthy volunteers, diminished area under the hydroxylamine plasma concentration-time curve by 65%, apparent formation clearance of the hydroxylamine by 71%, and clearance of dapsone by 26%. Disulfiram produced a 78% lower concentration of methemoglobin 8 hours after dapsone.

Inhibition of sulfamethoxazole hydroxylamine formation by fluconazole in human liver microsomes and healthy volunteers.

Sulfamethoxazole toxicity is putatively initiated by the formation of a hydroxylamine metabolite by cytochromes P450. If this reaction could be inhibited, toxicity may decrease. We have studied--in vitro and in vivo--fluconazole, ketoconazole, and cimetidine as potentially suitable clinical inhibitors of sulfamethoxazole hydroxylamine formation. Both fluconazole and ketoconazole in human liver microsomal incubations competitively inhibited sulfamethoxazole N-hydroxylation, with the inhibitory constant (Ki) values of 3.5 and 6 micromol/L, respectively. Cimetidine exhibited a mixed type of inhibition of sulfamethoxazole hydroxylamine formation in human liver microsomes, with IC 50 values (the concentration required to decrease hydroxylamine formation by 50%) of 80 and 800 micromol/L, the lower value being observed when cimetidine was preincubated with microsomes and reduced nicotinamide adenine dinucleotide phosphate. In an in vivo study in six healthy volunteers the inhibition of the cytochrome P450-mediated generation of the toxic metabolite in the presence of fluconazole was shown by a 94% decrease in the area under the plasma concentration-time curve of sulfamethoxazole hydroxylamine. In contrast, the recovery of hydroxylamine in urine decreased by only 60%. Total clearance of sulfamethoxazole was decreased by 26% by fluconazole, most likely because of the inhibition of unidentified P450 elimination pathways. There was close agreement between the predicted (87%) and observed inhibition (94%) of sulfamethoxazole hydroxylamine formation in vivo. Similarly, there was close agreement between in vivo and in vitro Ki values--1.6 and 3.5 micron/L, respectively.

Pharmacokinetics of dideoxyinosine in pigtailed macaques (Macaca nemestrina) after intravenous and subcutaneous administration.

Four macaques (Macaca nemestrina; 1 female and 3 males) were administered dideoxyinosine (DDI) at three dose levels (3.2 mg/kg i.v., 10 mg/kg i.v., and 20 mg/kg s.c.). Blood and urine samples were collected during 6-8 h and 24 h after drug administration, respectively. The mean plasma clearance (16.7 +/- 4.9 ml/min/kg), steady-state volume of distribution (1.5 +/- 0.4 L/kg), and terminal plasma half-life (96.8 +/- 7.5 min) did not differ significantly between the two i.v. doses. DDI was eliminated from the body primarily by excretion of the unchanged drug in the urine (74%). The absorption of DDI from the subcutaneous site was complete (bioavailability of 0.91 +/- 0.13) and rapid, with peak plasma concentration obtained at 30 min.

Pharmacokinetics of zidovudine (azidothymidine). I. Transplacental transfer.

Administration of zidovudine (ZDV) to pregnant women with human immunodeficiency virus infection may be of benefit to both the mother and the unborn child. Before testing this hypothesis, however, it is necessary to determine the transplacental transfer, fetal toxicity, and fetal accumulation of ZDV (if any) in a representative animal model. Therefore, the transplacental transfer and the fetal accumulation of ZDV were determined at steady state in near-term pregnant macaques (Macaca nemestrina). ZDV was administered to five dams at a rate predicted to produce a steady-state plasma concentration of about 1 microgram/ml. When steady state was predicted to have been achieved, a cesarean section was performed on each dam. At this time, blood samples from the dam (peripheral vein) and the fetus (umbilical vein) were obtained simultaneously. The plasma concentration of ZDV and its major metabolite, zidovudine glucuronide (ZDVG), were determined by a specific high-performance liquid chromatography (HPLC) method. The ratio of steady-state plasma concentration (Crss) of ZDV in the fetus (Cssf) to that in the dam (Cssd) (Crss = Cssf/Cssd) was found to be close to unity (0.826 +/- 0.067). Similar results were obtained for the ratio of steady-state unbound ZDV plasma concentration (0.852 +/- 0.083). We conclude that ZDV readily crosses the placenta, probably by passive diffusion, and that ZDV does not accumulate in the fetus when administered to near-term pregnant macaques.

Pharmacokinetics of zidovudine (azidothymidine). II. Development of metabolic and renal clearance pathways in the neonate.

The pharmacokinetics of zidovudine (ZDV or azidothymidine) were investigated in newborn macaques (Macaca nemestrina) at various ages ranging from less than 1 week to 4 months. The mean ZDV total plasma clearance, renal clearance, and the metabolic clearance of ZDV to the glucuronide (ZDVG) were significantly (p less than 0.05) smaller during the first week of life (6.15 +/- 1.03, 4.25 +/- 0.36, and 1.19 +/- 0.67 ml/min/kg, respectively) than the corresponding estimates at the age of 4 months (19.62 +/- 3.5, 8.28 +/- 1.90, and 8.28 +/- 2.24 ml/min/kg, respectively). The mean estimates of these parameters at 4 months were close to those found in adult macaques (23.55 +/- 1.48, 10.05 +/- 0.75, and 10.5 +/- 1.9 ml/min/kg, respectively), indicating that these clearance pathways develop rapidly, within 4 months of birth. If similar results are obtained in human neonates, therapeutic drug monitoring should be instituted when administering ZDV to this population so that the dose of ZDV may be adjusted to correspond with age-related changes in total plasma clearance of ZDV.

Pharmacokinetics of zidovudine (azidothymidine). III. Effect of pregnancy.

Administration of zidovudine (ZDV or azidothymidine) to pregnant women with HIV infection may be of benefit to both the mother and her unborn child. Since pregnancy can have a substantial effect on the pharmacokinetics of a drug, the effect of pregnancy on the pharmacokinetics of ZDV (10 mg/kg, i.v. bolus) was studied in the macaque (Macaca nemestrina). The plasma clearance, steady-state volume of distribution, and terminal half-life of ZDV were found not to be significantly affected by pregnancy. Based on these findings, we predict that the pharmacokinetics of ZDV in women will not be affected by pregnancy. If this prediction is found to be correct, the dose of ZDV need not be adjusted when the drug is administered to pregnant women.