Grading Average = 91

Errata

Michaelis-Menten Derivation KmKm k cat Formation of ES complex is rapid (k cat <<k off ), therefore Rate Limiting

Michaelis-Menten Derivation KmKm k cat Formation of ES complex is rapid (k cat <<k off ), therefore Rate Limiting

Clarifications

Michaelis-Menten Assumptions Quasi-steady-state approximation – [ES] remains constant at saturating [S] – d[ES]/dt=0 (i.e. forward rate = reverse rate) [E]<<K m and [S] Rapid Equilibrium for the ES complex k cat << k off Product formation is irreversible KmKm k cat k on k off

20% Decrease in Dose (250 mg/day  200 mg/day) 50% decrease anti-seizure (a.k.a. Dilantin) Capacity-Limited Metabolism Excitatory Synapse

NON-LINEARITIES CONTINUED Lecture #35

Review Constant Rate Input IV Bolus Constant Rate Input

Review: Reasons Individualization – Pain – Low Therapeutic Index – Anesthesia Drug Solubility Rapid Degradation/Elimination  High Enough [Drug] plasma Maintain/Control Response Drug Toxicity  Control plasma levels

Review: Time to Reach Plateau 90% of the plateau value

Constant Rate Infusion t 90

Constant Rate Infusion: Plateau R o = constant rate input (mg/hr) KmKm VmVm Cu SS Higher K m (weaker)ConstantHigher Lower K m (tighter)ConstantLower ConstantHigher V m (inducing)Lower ConstantLower V m (inhibiting)Higher What does the extraction ratio have to be?

Constant Rate Infusion: Time to Plateau R o = constant rate input (mg/hr) Km’Km’ VmVm t 90 Higher K m (weaker)Constantlonger Lower K m (tighter)Constantshorter ConstantHigher V m (inducing)shorter ConstantLower V m (inhibiting)longer Basically, it has this correlation.

Concentration-Dependent Renal Excretion

penicillin antibiotic

Concentration-Dependent Renal Excretion A = GFR Only B = GFR and Active Secretion C = GFR and Active Reabsorption

GFR and Active Reabsorption

Saturable Binding to Plasma Proteins n = number of binding sites P t = protein concentration n*P t = concentration of drug binding sites KDKD Cu + Assumptions?

Non-linear binding to  1 -acid glycoprotein  1 -acid glycoprotein Na + channel inhibitor

Saturable Albumin Binding NSAID

Saturable Albumin Binding Binding to Albumin Cephalosporin Antibiotic

Saturable Plasma Protein Binding ACE Inhibitor Prodrug Trandolaprilat Active

Saturable Transport T m = maximum transport rate active or passive transport? Cu in Cu out KTKT

Saturable Tissue Binding endothelin receptor antagonist (ERA) Endothelin-1 ECE = Endothelin Converting Enzyme

Time-Dependent PK (Chronopharmacokinetics) Enzyme Induction Circadian variations – Renal Function, Urine pH,  1 -acid glycoprotein GI Physiology (Food and Drink) – Gastric emptying slowed/delayed by food Autoinduction Mechanism-based Autoinhibition

Chronopharmacokinetics: Renal Function aminoglycoside

Saturable Tissue Binding imirestat aldose reductase inhibitor glaucoma

Saturable Tissue Binding nucleoside transporter inhibitor

Chronopharmacokinetics: Food VDCC =Voltage-dependent Calcium Channel Verapamil Taken At Different Times of the Day

Chronopharmacokinetics: Mechanism- Based Autoinhibition

Chronopharmacokinetics: Autoinduction Excitatory Synapse anticonvulsant

Recognition of Non-linearities Compare with Linear Kinetics Identify altered Kinetic parameters Determine Primary PK parameters (e.g. k, V) Consistent with Mechanism

Assessment of Non-linearities Urine Recovery Concentration-Time Profile Protein Binding

Assessment of Non-linearities Salicylic Acid For Skin

Urine Recovery If Linear If Non-Linear

Concentration-Time Profile If Linear If Non-linear

Protein Binding If linear If Non-linear

Constant Rate Infusion

PK of a Drug Overdose CL T and V often changed t 1/2 increased – e.g. Ethchlorvynol 25 hrs  100 hrs Plasma rebound after dialysis – redistribution in fat (poorly perfused) hypnotic, euphoria insomnia

PK of a Drug Overdose Sedative/Hypnotic If Linear If Non-Linear * Plasma rebound due to redistribution. * schedule IV (USA) controlled cerebral depression mechanism of action is not known.

Therapeutic Consequences of Non- linearities Dose Dependence – Capacity-Limited Metabolism (Major) low E – Dissolution-Limited  Bioavailability – GI physiology  Bioavailability Chronopharmacokinetics – Autoinduction – Mechanism-based Inhibition